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original article
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 355;23 www.nejm.org december 7, 20062408
Five-Year Follow-up of Patients Receiving
Imatinib for Chronic Myeloid Leukemia
Brian J. Druker, M.D., François Guilhot, M.D., Stephen G.
O’Brien, M.D., Ph.D.,
Insa Gathmann, M.Sc., Hagop Kantarjian, M.D., Norbert
Gattermann, M.D.,
Michael W.N. Deininger, M.D., Ph.D., Richard T. Silver, M.D.,
John M. Goldman, D.M., Richard M. Stone, M.D., Francisco
Cervantes, M.D.,
Andreas Hochhaus, M.D., Bayard L. Powell, M.D., Janice L.
Gabrilove, M.D.,
Philippe Rousselot, M.D., Josy Reiffers, M.D., Jan J.
Cornelissen, M.D., Ph.D.,
Timothy Hughes, M.D., Hermine Agis, M.D., Thomas Fischer,
M.D.,
Gregor Verhoef, M.D., John Shepherd, M.D., Giuseppe Saglio,
M.D.,
Alois Gratwohl, M.D., Johan L. Nielsen, M.D., Jerald P.
Radich, M.D.,
Bengt Simonsson, M.D., Kerry Taylor, M.D., Michele
Baccarani, M.D.,
Charlene So, Pharm.D., Laurie Letvak, M.D.,

and Richard A. Larson, M.D., for the IRIS Investigators*
Address reprint requests to Dr. Druker at
the Oregon Health and Science University
Cancer Institute, L592, 3181 SW Sam Jack-
son Park Rd., Portland, OR 97239, or at
[email protected]
* Authors’ affiliations and investigators in
the International Randomized Study of
Interferon and STI571 (IRIS) are listed in
the Appendix.
N Engl J Med 2006;355:2408-17.
Copyright © 2006 Massachusetts Medical Society.
A B S T R A C T
Background
The cause of chronic myeloid leukemia (CML) is a
constitutively active BCR-ABL tyro-
sine kinase. Imatinib inhibits this kinase, and in a short-term
study was superior to
interferon alfa plus cytarabine for newly diagnosed CML in the
chronic phase. For
5 years, we followed patients with CML who received imatinib
as initial therapy.
Methods
We randomly assigned 553 patients to receive imatinib and 553
to receive interferon
alfa plus cytarabine and then evaluated them for overall and
event-free survival; pro-
gression to accelerated-phase CML or blast crisis; hematologic,
cytogenetic, and mo-

lecular responses; and adverse events.
Results
The median follow-up was 60 months. Kaplan–Meier estimates
of cumulative best
rates of complete cytogenetic response among patients receiving
imatinib were 69%
by 12 months and 87% by 60 months. An estimated 7% of
patients progressed to
accelerated-phase CML or blast crisis, and the estimated overall
survival of patients
who received imatinib as initial therapy was 89% at 60 months.
Patients who had a
complete cytogenetic response or in whom levels of BCR-ABL
transcripts had fallen
by at least 3 log had a significantly lower risk of disease
progression than did pa-
tients without a complete cytogenetic response (P<0.001).
Grade 3 or 4 adverse events
diminished over time, and there was no clinically significant
change in the profile
of adverse events.
Conclusions
After 5 years of follow-up, continuous treatment of chronic-
phase CML with imatinib
as initial therapy was found to induce durable responses in a
high proportion of pa-
tients. (ClinicalTrials.gov number, NCT00006343.)
The New England Journal of Medicine
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Copyright © 2006 Massachusetts Medical Society. All rights
reserved.
Im atinib a s Pr im a r y Ther a py for Chronic M y el oid Leuk
emi a
n engl j med 355;23 www.nejm.org december 7, 2006 2409
Chronic myeloid leukemia (cml) is a myeloproliferative
disorder characterized by the expansion of a clone of
hematopoi-
etic cells that carries the Philadelphia chromo-
some (Ph).1 The Ph chromosome results from a
reciprocal translocation between the long arms
of chromosomes 9 and 22, t(9;22)(q34;q11).2 The
molecular consequence of this translocation is a
novel fusion gene, BCR-ABL, which encodes a con-
stitutively active protein, tyrosine kinase.3-5 Ima-
tinib (Gleevec, Novartis; formerly called STI571) is
a relatively specific inhibitor of the BCR-ABL tyro-
sine kinase and has efficacy in CML.6-11
Before the availability of imatinib, interferon
alfa plus cytarabine was considered standard ther-
apy for patients with CML who were not plan-
ning to undergo allogeneic hematopoietic stem-
cell transplantation.12,13 A randomized trial that
compared imatinib with interferon alfa plus cyta-
rabine in the chronic phase of CML demonstrated
the significant superiority of imatinib in all stan-
dard indicators of the disease within a median
follow-up of 19 months.14 The trial was designed
as a crossover study, and given the superior results
with imatinib, a large proportion of patients in

the interferon group switched to imatinib. In ad-
dition, at the time of Food and Drug Administra-
tion approval of imatinib, many patients who were
assigned to receive interferon alfa plus cytarabine
left the study. Consequently, the trial has evolved
into a long-term study of the result of treating
newly diagnosed patients in the chronic phase of
CML with imatinib. We now report 60 months of
follow-up data and focus on patients who received
imatinib as a primary treatment.
M e t h o d s
Study Design
The design of the study has been described pre-
viously.14 The International Randomized Study
of Interferon and STI571 (IRIS) was a multicenter,
international, open-label, phase III randomized
study. Eligible patients had to be between 18 and
70 years of age, must have been diagnosed with
Ph-positive CML in chronic phase within 6 months
before study entry, and must not have received
treatment for CML, except for hydroxyurea or ana-
grelide.
Patients were recruited from June 2000 through
January 2001 and were randomly assigned to re-
ceive imatinib at a dose of 400 mg orally per day
or subcutaneous interferon alfa at a daily tar-
get dose of 5 million U per square meter of body-
surface area, plus 10-day cycles of cytarabine at
a daily dose of 20 mg per square meter every
month. Patients receiving imatinib who did not
have a complete hematologic response within

3 months or whose bone marrow contained more
than 65% Ph-positive cells at 12 months could
have a stepwise increase in the dose of imatinib
to 400 mg orally twice daily as long as there were
no dose-limiting adverse events. Patients were al-
lowed to cross over to the other treatment group
if they did not achieve either a complete hema-
tologic response after 6 months of therapy or a
major cytogenetic response after 12 months or if
they had a relapse or an increase in white-cell
count or could not tolerate treatment. All cross-
over requests were made anonymously and con-
sidered weekly by the study management com-
mittee (see the Appendix).
End Points
The primary end point was event-free survival,
which was referred to in previous presentations
and articles as the time to progression, or progres-
sion-free survival. Events were defined by the first
occurrence of any of the following: death from any
cause during treatment, progression to the acceler-
ated phase or blast crisis of CML, or loss of a com-
plete hematologic or major cytogenetic response.
Secondary end points were the rate of complete he-
matologic response (defined as a leukocyte count
<10×109 per liter, a platelet count of <450×109 per
liter, <5% myelocytes plus metamyelocytes, no
blasts or promyelocytes, no extramedullary involve-
ment, and no signs of the accelerated phase or
blast crisis of CML); a cytogenetic response in mar-
row cells, categorized as complete (no Ph-positive
metaphases), partial (1 to 35% Ph-positive meta-
phases), or major (complete plus partial responses)
on the basis of G-banding in at least 20 cells in

metaphase per sample; progression to the acceler-
ated phase or blast crisis; overall survival; safety;
and tolerability. Signs of a molecular response were
sought every 3 months after a complete cytoge-
netic response was obtained with the use of real-
time quantitative polymerase chain reaction to
measure the ratio of BCR-ABL transcripts to BCR
transcripts. Results were expressed as “log reduc-
tions” below a standardized baseline derived from
reserved.
a median ratio of BCR-ABL to BCR obtained from
30 untreated patients with chronic-phase CML.15
Ethics and Study Management
The study was conducted in accordance with the
Declaration of Helsinki. The study protocol was
reviewed by the ethics committee or institutional
review board at each participating center. All pa-
tients gave written informed consent, according
to institutional regulations. The academic inves-
tigators and representatives of the sponsor, No-

vartis, designed the study. Data-management and
statistical-support staff at a contract research or-
ganization collected the data, which were ana-
lyzed and interpreted by a biostatistician from No-
vartis in close collaboration with the investigators.
The study management committee and all aca-
demic investigators had access to the raw data. The
study management committee, composed of four
academic investigators, served as the writing com-
mittee. Along with the Novartis biostatistician,
they vouch for the accuracy and completeness of
the data.
Statistical Analysis
The study is ongoing, but January 31, 2006, was
the cutoff date for this analysis. This date marked
5 to 5.5 years after patients started to receive ima-
tinib treatment. We followed all 553 patients who
were assigned to receive imatinib for an analysis
of safety and efficacy until they stopped taking
imatinib, and we have continued to follow all pa-
tients until death, loss to follow-up, or withdraw-
al of consent. Survival data were also collected on
patients who underwent bone marrow transplan-
tation after imatinib treatment. We performed
analyses of survival and event-free survival, using
the Kaplan–Meier method according to the inten-
tion-to-treat principle and using all data available,
regardless of whether crossover occurred. Differ-
ences between subgroups of patients receiving
imatinib were calculated by the log-rank test. Cu-
mulative rates of complete hematologic and cyto-
genetic responses were estimated according to the
Kaplan–Meier method, in which data from patients
receiving imatinib who did not have an adequate

response, who had switched to interferon alfa plus
cytarabine, or who had discontinued treatment for
reasons other than progression of CML were cen-
sored at the last follow-up visit. For the estimation
of cumulative response rates, we censored data
from patients with progressive CML at maximum
follow-up. We used the life-table method to deter-
mine yearly event probabilities. The safety of ima-
tinib was analyzed for 551 patients who received
at least one dose of the study drug during the trial.
For the 553 patients assigned to receive interfer-
on alfa plus cytarabine, disposition and overall sur-
vival were summarized.
Table 1. Enrollment, Outcomes, and Reasons for Crossover
and Discon tinuation.*
Variable
Imatinib
(N = 553)
Interferon Alfa
plus Cytarabine
(N = 553)
no. of patients (%)
Assignment of patients
Continued first-line treatment 382 (69) 16 (3)
Discontinued first-line treatment 157 (28) 178 (32)
Crossed over to other treatment 14 (3) 359 (65)

Discontinued second-line treatment 14 (3) 108 (20)
Reason for crossover
Other than progression
Intolerance of treatment† 4 (<1) 144 (26)
No complete hematologic
response at 6 mo
0 41 (7)
No major cytogenetic response
at 12 mo
1 (<1) 49 (9)
Other 0 48 (9)
Progression only
Increase in white-cell count† 2 (<1) 25 (5)
Loss of complete hematologic
response
5 (<1) 29 (5)
Loss of major cytogenetic
response
2 (<1) 23 (4)
Reason for discontinuation‡

Adverse event 23 (4) 35 (6)
Death 10 (2) 2 (<1)
Unsatisfactory therapeutic effect 59 (11) 29 (5)
Stem-cell transplantation 16 (3) 7 (1)
Protocol violation 15 (3) 17 (3)
Loss to follow-up 5 (<1) 6 (1)
Withdrawal of consent 25 (5) 76 (14)
Other 4 (<1) 6 (1)
* The first patient entered the study on June 16, 2000, and
enrollment ended
January 30, 2001.
† The crossover of patients with this condition to the other
treatment group
needed previous approval by the study management committee.
‡ A total of 157 patients who received imatinib and 178 patients
who received
interferon alfa plus cytarabine discontinued therapy.
reserved.

emi a
R e s u l t s
Patients
Five years after the last of 1106 patients had started
treatment, and with a median of 60 months of
follow-up, 382 of 553 patients (69%) in the ima-
tinib group and 16 of 553 patients (3%) in the
group given interferon alfa plus cytarabine con-
tinued with their initially assigned treatment (Ta-
ble 1). Of the patients given interferon plus cyta-
rabine, 359 (65%) had crossed over to imatinib,
whereas 14 patients (3%) in the imatinib group
had switched to the alternative treatment. The most
common reason for crossover among patients
given interferon plus cytarabine was intolerance
of treatment (26%). Of these patients, 90 (16%)
switched because they did not achieve a complete
hematologic or major cytogenetic response by the
designated target dates, as did 77 patients (14%)
with disease progression. An additional 178 pa-
tients (32%) given interferon alfa plus cytarabine
discontinued therapy. The reasons most common-
ly reported were withdrawal of consent (14%) and
adverse events (6%). In the imatinib group, 23 pa-
tients (4%) discontinued therapy owing to an ad-
verse event, and 25 patients (5%) withdrew con-
sent (Table 1).
Since few patients were still receiving inter-

feron alfa plus cytarabine at 60 months, the re-
mainder of this report focuses on the long-term
follow-up of patients who received imatinib as
the initial therapy for CML. They had been treated
with imatinib for a mean (±SD) of 50±19 months
(median, 60 months). Among the 382 patients
who continued receiving imatinib, the mean daily
dose during this reporting period was 382±50 mg.
In 82% of these patients, the last reported daily
dose was 400 mg; 6% were receiving 600 mg, 4%
were receiving 800 mg, and 8% were receiving
less than 400 mg.
Table 2. Proportion of Patients Receiving First-Line Imatinib
Therapy with Grade 3 or Grade 4 Adverse Events.
Hematologic or Hepatic Condition Grade 3 or Grade 4 Adverse
Events
Total Events
(N = 551)
Years 1 and 2
(N = 551)
Years 3 and 4
(N = 456)
After Year 4
(N = 409)
percent
Neutropenia 17 14 3* 1*

Thrombocytopenia 9 8 1* <1*
Anemia 4 3 1† <1‡
Elevated liver enzymes 5 5 <1* 0*
Other drug-related adverse event 17 14 4* 2*
* P<0.001 for the comparison of events in years 3 and 4 and
after 4 years with those in years 1 and 2.
† The difference between events in years 3 and 4 and those in
years 1 and 2 did not reach statistical significance.
‡ P<0.01 for the comparison of events after 4 years with those
in years 1 and 2.
22p3
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Complete hematologic response
Major cytogenetic response
Complete cytogenetic response
Figure 1. Kaplan–Meier Estimates of the Cumulative Best
Response
to Initial Imatinib Therapy.
At 12 months after the initiation of imatinib, the estimated rates
of having
a response were as follows: complete hematologic response,
96%; major
cytogenetic response, 85%; and complete cytogenetic response,
69%. At
60 months, the respective rates were 98%, 92%, and 87%. Data
for pa-
tients who discontinued imatinib for reasons other than
progression and
who did not have an adequate response were censored at the last
follow-up
visit. Data for patients who did not have an adequate response
and who
stopped imatinib because of progression were censored at
maximum fol-
low-up.

reserved.
Adverse Events
After a median follow-up of 60 months, the ad-
verse events reported were similar to those report-
ed previously.14 The most commonly reported ad-
verse events were edema (including peripheral and
periorbital edema) (60%), muscle cramps (49%),
diarrhea (45%), nausea (50%), musculoskeletal
pain (47%), rash and other skin problems (40%),
abdominal pain (37%), fatigue (39%), joint pain
(31%), and headache (37%). Grade 3 or 4 adverse
events consisted of neutropenia (17%), throm-
bocytopenia (9%), anemia (4%), elevated liver en-
zymes (5%), and other drug-related adverse events
(17%). Congestive heart failure was reported as
being drug-related in one patient (<1%). Newly oc-
curring or worsening grade 3 or 4 hematologic or
biochemical adverse events were infrequent after
both 2 and 4 years of therapy (Table 2).
Efficacy
Figure 1 shows the estimated cumulative rates
of complete hematologic remission: 96% at 12
months and 98% at 60 months. The best observed
rate of complete hematologic response was 97%.
At 12 months, the estimated rate of major cyto-

genic response was 85% and that of complete cy-
togenetic response was 69%. At 60 months, the
estimated rates were 92% and 87%, respectively.
With a median follow-up of 60 months, the best
observed rate of major cytogenetic response was
89%, and the best rate of complete cytogenetic
response was 82%. Of the 382 patients who still
received imatinib at 60 months, 368 (96%) had a
complete cytogenetic response.
There were significant differences in the rates
of cytogenetic response, according to a scoring
system devised by Sokal and colleagues,16 which
divides patients with CML into low-risk, interme-
diate-risk, and high-risk groups. In patients who
were deemed to be at low risk on the Sokal scor-
ing system, the rate of complete cytogenetic re-
sponse was 89%; the rate among patients at in-
termediate risk was 82%; and for those at high
risk, the rate was 69% (P<0.001).
Among 124 patients who had a complete cy-
togenetic response and whose blood samples tak-
en at 1 and 4 years were available, BCR-ABL tran-
scripts in the blood samples were measured. After
1 year, levels of BCR-ABL transcripts had fallen by
at least 3 log in 66 of 124 patients (53%); after
4 years, levels had fallen in 99 of 124 patients
(80%) (P<0.001). The proportion of patients with
a reduction of at least 4 log in transcript levels
increased from 22 to 41% between 1 and 4 years
(P<0.001). The median log reduction of BCR-ABL
transcripts was 3.08 at 1 year and 3.78 at 4 years
(P<0.001).
Long-term Outcomes

At 60 months, the estimated rate of event-free sur-
vival was 83% (95% confidence interval [CI], 79
to 87), and an estimated 93% of patients (95% CI,
90 to 96) had not progressed to the accelerated
phase or blast crisis (Fig. 2). Of the 553 patients
receiving imatinib, 35 (6%) progressed to the ac-
celerated phase or blast crisis, 14 (3%) had a he-
matologic relapse, 28 (5%) had a loss of major cy-
togenetic response, and 9 (2%) died from a cause
unrelated to CML. The estimated annual rate of
treatment failure after the start of imatinib ther-
apy was 3.3% in the first year, 7.5% in the second
year, 4.8% in the third year, 1.5% in the fourth
year, and 0.9% in the fifth year. The correspond-
ing annual rates of progression to the accelerated
phase or blast crisis were 1.5%, 2.8%, 1.6%, 0.9%,
and 0.6%, respectively. In the 454 patients who had
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Progression
All events
No. of Events
Progression
All events
No. at Risk
Progression
All events
8
18
513
505
22
55
461
447
29
76

431
414
33
82
409
395
35
85
280
274
Figure 2. Kaplan–Meier Estimates of the Rates of Event-free
Survival
and Progression to the Accelerated Phase or Blast Crisis of
CML for Pa-
tients Receiving Imatinib.
At 60 months, the estimated rate of event-free survival was
83%. At that
time, 93% of the patients had not progressed to the accelerated
phase or
blast crisis. The following were considered events: death from
any cause
during treatment, progression to the accelerated phase or blast
crisis, loss
of a complete hematologic response, loss of a major cytogenetic
response,
or an increasing white-cell count. The number of patients with
events and
the number of patients available for analysis are shown.

reserved.
emi a
a complete cytogenetic response, the annual rates
of treatment failure were 5.5% in the first year,
2.3% in the second year, 1.1% in the third year,
and 0.4% in the fourth year after a response was
achieved. The corresponding annual rates of pro-
gression to the accelerated phase or blast crisis
were 2.1%, 0.8%, 0.3%, and 0%, respectively, in
these patients.
Effect of Response on Outcome
Cytogenetic and molecular responses had signifi-
cant associations with event-free survival and de-
terrence against progression to the accelerated
phase or blast crisis (Fig. 3). A landmark analysis
of the 350 patients who had had a complete cyto-
genetic response at 12 months after the initiation
of imatinib treatment revealed that at 60 months,
97% of the patients (95% CI, 94 to 99) had not
progressed to the accelerated phase or blast crisis.
For the 86 patients with a partial cytogenetic re-
sponse, the estimate was 93% (95% CI, 87 to 99);

for the 73 patients who did not have a major cy-
togenetic response within 12 months, the esti-
mate was 81% (95% CI, 70 to 92) (overall, P<0.001;
P<0.001 for the comparison between patients with
a complete response and those without a com-
plete response, and P = 0.20 for the comparison
between patients with a complete response and
those with a partial response) (Fig. 3A).
At 60 months, the estimated risk of disease
progression was significantly higher for the high-
risk group of patients, according to the Sokal
scoring system (P = 0.002); the estimated rates for
patients in the high-risk, intermediate-risk, and
low-risk groups were 17%, 8%, and 3%, respec-
tively. However, the Sokal score was not associ-
ated with disease progression in patients who had
a complete cytogenetic response (95%, 95%, and
99% in the high-risk, intermediate-risk, and low-
risk groups, respectively) (P = 0.20 overall; P = 0.92
for the comparison between the intermediate-risk
group and the high-risk group, and P = 0.16 for the
comparison between the low-risk group and the
high-risk group).
The molecular responses at 12 and 18 months
were also associated with long-term outcomes. At
60 months, the patients who had a complete cyto-
genetic response and a reduction of at least 3 log
in levels of BCR-ABL transcripts in bone marrow
cells after 18 months of treatment had an esti-
mated rate of survival without progression of CML
of 100%. In the group with a reduction of less
22p3

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with ≥3 log reduction
with <3 log reduction
No complete cytogenetic response
A
B
Partial cytogenetic response
No major cytogenetic response
Response at 12 Mo

Response at 18 Mo
Figure 3. Rate of Progression to the Accelerated Phase or Blast
Crisis
on the Basis of Cytogenetic Response after 12 Months or
Molecular
Response after 18 Months of Imatinib Therapy.
Panel A shows that at 60 months, of the 350 patients with a
complete cyto-
genetic response after 12 months of imatinib therapy, an
estimated 97%
had not progressed to the accelerated phase or blast crisis. The
corre-
sponding rates for 86 patients with a partial cytogenetic
response and for
73 patients who did not have a major cytogenetic response were
93% and
81%, respectively (P<0.001; P = 0.20 for the comparison
between patients
with a complete cytogenetic response and those with a partial
response).
At 12 months, 44 patients had discontinued imatinib and thus
were not
included in this analysis. Panel B shows that at 60 months, of
the 139 pa-
tients with a complete cytogenetic response and a reduction in
levels of
BCR-ABL transcripts of at least 3 log, 100% were free from
progression to
the accelerated phase or blast crisis. The corresponding rate for
54 patients
with a complete cytogenetic response and a reduction in levels
of BCR-ABL
transcripts of less than 3 log was 98%; the rate for 88 patients
without a

complete cytogenetic response was 87% (P<0.001; P = 0.11 for
the compari-
son between patients with a major molecular response and those
without
a major molecular response). At 18 months, 86 patients had
discontinued
imatinib and 186 patients had achieved a complete cytogenetic
response
but did not have a PCR result available.
reserved.
than 3 log in levels of BCR-ABL transcripts, the es-
timated rate was 98% (P = 0.11). However, in the
absence of a complete cytogenetic response, the
rate was 87% (P<0.001) (Fig. 3B). No patient who
had a complete cytogenetic response and reduc-
tion of at least 3 log in levels of BCR-ABL transcripts
at 12 months had progressed to the accelerated
phase or blast crisis at 60 months.
Overall Survival
By the cutoff date for this analysis, 57 patients
(10%) who received imatinib had died; 5 of these

patients had switched to interferon alfa plus cy-
tarabine. The estimated overall survival rate at 60
months was 89% (95% CI, 86 to 92) (Fig. 4). Allo-
geneic hematopoietic stem-cell transplantation
was carried out in 44 patients who discontinued
imatinib: 11 had progressed to the accelerated
phase or blast crisis, 15 had had a hematologic or
cytogenetic relapse, and 18 had stopped therapy
for other reasons (including safety and withdrawal
of consent). Of the 44 patients who underwent
transplantation, 14 (32%) died. At 60 months, with
data censored at the time of transplantation, the
estimated overall survival rate was 92% (95% CI,
89 to 95). After data were censored for patients
who had died from causes unrelated to CML or
transplantation, the overall estimated survival rate
was 95% (95% CI, 93 to 98) at 60 months (Fig. 4).
D i s c u s s i o n
The initial analysis of this study, performed at a
median follow-up of 19 months, showed a high
rate of response and an acceptable rate of side ef-
fects of imatinib as initial therapy for newly diag-
nosed chronic-phase CML.14 The present analysis,
with a median follow-up of 60 months, showed
an estimated relapse rate of 17% at 60 months, and
an estimated 7% of all patients progressed to the
accelerated phase or blast crisis. The 5-year esti-
mated overall survival rate for patients who re-
ceived imatinib as initial therapy (89%) is higher
than that reported in any previously published pro-
spective study of the treatment of CML.17
This trial allowed patients to cross over to the

alternate treatment, and most patients in the in-
terferon group either switched to imatinib or dis-
continued interferon. On the basis of an inten-
tion-to-treat analysis, there was no significant
difference in overall survival between the group
of patients who began their treatment with inter-
feron and those who began their treatment with
imatinib (data not shown). Previous randomized
studies of interferon alfa plus cytarabine, per-
formed before the availability of imatinib, showed
a 5-year overall survival of 68 to 70%.12,13 With the
use of historical comparisons, a survival advan-
tage for initial therapy with imatinib over inter-
feron alfa can be demonstrated.18
In a landmark analysis, 97% of patients with
a complete cytogenetic response within 12 months
after starting imatinib did not progress to the ac-
celerated phase or blast crisis by 60 months. No-
tably, patients who were deemed to be at high risk
on the basis of Sokal scores had a lower rate of
complete cytogenetic response (69%) than did pa-
tients who were at low risk or intermediate risk
(89% and 82%, respectively). However, the risk of
relapse in patients who had a cytogenetic response
was not associated with the Sokal score. With
interferon treatment, by contrast, the Sokal score
was important even among patients with a com-
plete cytogenetic response.19
Remarkably, no patient who had a complete
cytogenetic response and a reduction in levels of
BCR-ABL transcripts of at least 3 log at 12 or 18
months after starting imatinib had progression
22p3

O
ve
ra
ll
S
u
rv
iv
al
(
%
)
80
90
70
60
40
30
10
50
20

0
0 12 24 36 48 60 72
Months
100
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail Line
H/T
Combo
Revised

REG F
Enon
1st
2nd
3rd
Druker
4 of 4
12-07-06
ARTIST: ts
35523
CML-related deaths
All deaths
No. of Deaths
Related to CML
All deaths
No. at Risk
Related to CML
All deaths
3
6
536
542

11
22
498
518
16
41
474
492
19
52
450
475
23
57
322
333
Figure 4. Overall Survival among Patients Treated with Imatinib
Based
on an Intention-to-Treat Analysis.
The estimated overall survival rate at 60 months was 89%. After
the cen-
soring of data for patients who died from causes unrelated to
CML or trans-
plantation, the estimated overall survival was 95% at 60
months. At the
time of analysis, 57 patients had died. The number of patients
with events

and the number of patients available for analysis are shown.
reserved.
emi a
of CML by 60 months. Only 2% of patients who
had a complete cytogenetic response and a reduc-
tion in levels of BCR-ABL transcripts of less than
3 log at 18 months had progressed to the accel-
erated phase or blast crisis at 60 months.
It is currently recommended that imatinib
therapy be continued indefinitely. Anecdotal re-
ports suggest that the discontinuation of imatinib,
even in patients with undectectable levels of BCR-
ABL transcripts, results in relapse.20-24 Although
it is not known why imatinib is not able to eradi-
cate the malignant clone, potential mechanisms
include drug efflux25 and amplification or muta-
tion of the BCR-ABL gene.26 It is also possible that
imatinib cannot completely inhibit BCR-ABL ki-
nase activity; low levels of activity would allow
cells to survive but not proliferate. As an alterna-
tive, the malignant clone could persist through
mechanisms that are independent of the BCR-ABL

kinase.27
Initial studies of two new inhibitors of the
BCR-ABL kinase that are more potent than ima-
tinib — dasatinib and nilotinib — showed high
response rates in patients who had had a relapse
during imatinib therapy.28,29 Despite their poten-
cy, these inhibitors cannot eradicate all CML cells
in vitro.30 As was the case in patients in our study,
it is assumed that in patients receiving these drugs
a durable response can be achieved even without
disease eradication if there is a reduction in lev-
els of BCR-ABL transcripts of at least 3 log.
Notably, the rate of disease progression in pa-
tients in our study is apparently trending down-
ward, although the trend has not reached statis-
tical significance. If it persists, such a trend would
be consistent with the findings that mutations
in the BCR-ABL gene are the major cause of relapse
in patients treated with imatinib.31 If we presume
that mutations precede imatinib therapy (as the
data suggest),32,33 the emergence of resistance to
the drug would depend on the size of the mutant
clone at the start of therapy and its doubling
time. Since most mutated and unmutated BCR-
ABL clones have similar doubling times,34 a pa-
tient with a mutant clone should be at highest risk
for relapse during the first several years of thera-
py. This prediction is in line with the apparent
downward trend in the risk of disease progres-
sion observed in our study.
Dr. Druker’s institution is the site of clinical trials sponsored
by Novartis, but neither he nor his laboratory reports receiving

funds from Novartis. Dr. Guilhot reports receiving consulting
and lecture fees from Novartis; Dr. O’Brien, consulting fees
from
Novartis and Bristol-Myers Squibb and lecture fees from Novar-
tis; Ms. Gathmann, being an employee of and having equity
ownership in Novartis; Dr. Kantarjian, consulting fees from No-
vartis, Bristol-Myers Squibb, and MGI Pharma; Dr. Gattermann,
consulting and lecture fees from Novartis and Pharmion; Dr.
Deininger, consulting and lecture fees from Novartis and Bris-
tol-Myers Squibb; Dr. Silver, consulting fees from Novartis; Dr.
Goldman, lecture fees from Novartis; Dr. Stone, consulting and
lecture fees and grant support from Novartis and Bristol-Myers
Squibb; Dr. Cervantes, consulting fees from Novartis and lec-
ture fees from Novartis and Bristol-Myers Squibb; Dr.
Hochhaus,
consulting and lecture fees from Novartis and Bristol-Myers
Squibb; Dr. Powell, lecture fees from Pharmion; Dr. Gabrilove,
consulting fees from Novartis; Dr. Rousselot, lecture fees from
Novartis Oncology; Dr. Cornelissen, consulting fees from
Novar-
tis Oncology; Dr. Hughes, consulting and lecture fees from No-
vartis; Dr. Fischer, consulting fees from LymphoSign and
Novar-
tis and lecture fees from Novartis; Dr. Saglio, consulting and
lecture fees from Novartis; Dr. Gratwohl, consulting fees from
Novartis, Pfizer, and Amgen and lecture fees from Novartis; Dr.
Radich, consulting fees from Novartis and Bristol-Myers Squibb
and lecture fees from Novartis; Dr. Simonsson, consulting fees
from Novartis and Bristol-Myers Squibb; Dr. Taylor, consulting
fees from Amgen, Novartis, Bristol-Myers Squibb, and Celgene
and lecture fees from Novartis; Dr. Baccarani, consulting fees
from Novartis, Bristol-Myers Squibb, Merck, and Pfizer and
lecture fees from Novartis, Bristol-Myers Squibb, Schering, and
Pfizer; Dr. So, being an employee of Novartis and having equity
ownership in Novartis and Pfizer; Dr. Letvak, being an
employee

of and having equity ownership in Novartis; and Dr. Larson,
consulting and lecture fees from Novartis. No other potential
conflict of interest relevant to this article was reported.
We thank the coinvestigators; the members of the medical,
nursing, and research staff at the trial centers; the clinical trial
monitors and the data managers and programmers at Novartis
for their contributions; and Tillman Krahnke and Manisha
Mone for their invaluable collaboration.
Appendix
From the Oregon Health and Science University Cancer
Institute, Portland (B.J.D.); Centre Hospitalier Universitaire,
Poitiers, France
(F.G.); University of Newcastle, Newcastle, United Kingdom
(S.G.O.); Novartis, Basel, Switzerland (I.G.); M.D. Anderson
Cancer Center,
Houston (H.K.); Heinrich Heine University, Dusseldorf,
Germany (N.G.); Universität Leipzig, Leipzig, Germany
(M.W.N.D.); Weill–Cor-
nell Medical Center, New York (R.T.S.); National Heart, Lung,
and Blood Institute, Bethesda, MD (J.M.G.); Dana–Farber
Cancer Institute,
Boston (R.M.S.); Hospital Clinic I Provincial, Barcelona (F.C.);
University of Heidelberg, Mannheim, Germany (A.H.); Wake
Forest Uni-
versity Baptist Medical Center, Winston-Salem, NC (B.L.P.);
Mount Sinai School of Medicine, New York (J.L.G.); Hôpital
Saint Louis,
Paris (P.R.); Centre Hospitalier Universitaire de Bordeaux,
Pessac, France (J.R.); Erasmus Medical Center, Rotterdam, the
Netherlands
(J.J.C.); Royal Adelaide Hospital, Adelaide, Australia (T.H.);
Universitätsklinik für Innere Medizin I, Vienna (H.A.);
Johannes Gutenberg
Universität, Mainz, Germany (T.F.); University Hospital

Gasthuisberg, Leuven, Belgium (G.V.); Vancouver Hospital,
Vancouver, BC, Cana-
da (J.S.); Azienda Ospedaliera S. Luigi Gonzaga, Orbassano,
Italy (G.S.); University Hospital Basel, Switzerland (A.G.);
Aarhus
Amtssygehus, Aarhus, Denmark (J.L.N.); Fred Hutchinson
Cancer Research Center, Seattle (J.P.R.); Akademiska
Sjukhuset, Uppsala, Swe-
den (B.S.); Mater Hospital, Brisbane, Australia (K.T.);
Policlinico S. Orsola–Malpighi, Bologna, Italy (M.B.);
Novartis, Florham Park, NJ
(C.S., L.L.); and University of Chicago, Chicago (R.A.L.).
reserved.
The following investigators participated in IRIS: Australia —
Royal Brisbane Hospital, Herston: S. Durrant; Monash Medical
Centre, Mel-
bourne: A. Schwarer; Sir Charles Gairdner Hospital, Perth: D.
Joske; Australian Leukemia and Lymphoma Group, Melbourne:
J. Seymour; Royal Mel-
bourne Hospital, Parkville: A. Grigg; St. Vincent’s Hospital,
Darlinghurst: D. Ma; Royal North Shore Hospital, St. Leonards:
C. Arthur; Westmead Hos-
pital, Westmead: K. Bradstock; Royal Prince Alfred Hospital,

Sydney: D. Joshua. Belgium — A.Z. Sint-Jan, Brugge: A.
Louwagie; Institut Jules Bordet,
Brussels: P. Martiat; Cliniques Universitaires, Yvoir: A. Bosly.
Canada — McGill University, Montreal: C. Shustik; Princess
Margaret Hospital, Toronto:
J. Lipton; Queen Elizabeth II Health Sciences Centre, Halifax,
NS: D. Forrest; McMaster University Medical Centre, West
Hamilton, ON: I. Walker; Uni-
versité de Montréal, Montreal: D.-C. Roy; CancerCare
Manitoba, Winnipeg: M. Rubinger; Ottawa Hospital Regional
Cancer Centre, Ottawa: I. Bence-
Bruckler; University of Calgary and Tom Baker Cancer Centre,
Calgary, AB: D. Stewart; London Regional Cancer Centre,
London, ON: M. Kovacs; Cross
Cancer Center, Edmonton, AB: A.R. Turner. Denmark —
Kobenhavns Amts Sygehus i Gentofte, Hellerup: H. Birgens;
Danish University of Pharmaceuti-
cal Sciences and University of Southern Denmark, Copenhagen:
O. Bjerrum. France — Hôpital Claude Huriez, Lille: T. Facon;
Hôtel Dieu Hospital, Nantes:
J.-L. Harousseau; Henri Mondor Hospital, Creteil: M. Tulliez;
Centre Hospitalier Universitaire (CHU) Brabois, Vandoeuvre-
les-Nancy: A. Guerci; Insti-
tut Paoli-Calmettes, Marseille: D. Blaise; Hopital Civil,
Strasbourg: F. Maloisel; CHU la Milétrie, Poitiers: M.
Michallet. Germany — University of
Regensburg, Regensburg: R. Andreesen; Krankenhaus
Muenchen Schwabing, Munich: C. Nerl; Universitätsklinikum
Rostock, Rostock: M. Freund;
Heinrich Heine University, Düsseldorf: N. Gattermann; Carl-
Gustav Carus Universität, Dresden: G. Ehninger; Leipzig
University Hospital, Leipzig: M.
Deininger; Medizinische Klinik III, Frankfurt: O. Ottmann;
Clinical Center Rechts der Isar, Munich: C. Peschel; University
of Heidelberg, Heidelberg: S.
Fruehauf; Philipps-Universität Marburg, Baldingerstraße,

Marburg: A. Neubauer; Humboldt Universität, Berlin: P. Le
Coutre; Robert Bosch Hospital,
Stuttgart: W. Aulitzky. Italy — University Hospital, Udine: R.
Fanin; San Orsola Hospital, Bologna: G. Rosti; Università La
Sapienza, Rome: F.
Mandelli; Istituto di Ricovero e Cura a Carattere Scientifico
(IRCCS) Policlinico San Matteo, Pavia: M. Lazzarino; Niguarda
Ca’ Granda Hospital, Milan:
E. Morra; Azienda Ospedaliera e Cliniche Universitarie San
Martino, Largo R Benzi, Genoa: A. Carella; University of Pisa,
Pisa: M. Petrini; Azienda Os-
pedaliera Bianchi-Malacrino-Morelli, Reggio Calabria: F.
Nobile; University of Bari, Policlinico, Bari: V. Liso; Cardarelli
Hospital, Naples: F. Ferrara;
University of Parma, Parma: V. Rizzoli; Ospedale Civile,
Pescara: G. Fioritoni; Institute of Hematology and Medical
Oncology Seragnoli, Bologna: G.
Martinelli; Università degli Studi di Firenze, Florence: V.
Santini. the Netherlands — Vrije Universiteit Academic
Medical Center, Amsterdam: G. Os-
senkoppele. New Zealand — University of Auckland, Auckland:
P. Browett. Norway — Medisinsk Avdeling, Rikshospitalet,
Oslo: T. Gedde-Dahl;
Ullevål Sykehus, Oslo: J.-M. Tangen; Hvidovre Hospital,
Betalende: I. Dahl. Spain — Hospital Clinic, Villarroel,
Barcelona: J. Odriozola; University of
Barcelona, Barcelona: J.C. Hernández Boluda; Hospital
Universitario de la Princesa, Madrid: J.L. Steegman; Hospital
Universitario de Salamanca,
Salamanca: C. Cañizo; San Carlos Clinical Hospital, Madrid: J.
Diaz; Institut Català d’Oncología, Barcelona: A. Granena;
Hospital Lluis Alcanyis, Cta
Xativa-Silla: M.N. Fernández. Sweden — Karolinska Hospital,
Stockholm: L. Stenke; Huddinge Sjukhus, Huddinge: C. Paul;
Medicinkliniken Uni-
versitetssjukhuset, Örebro: M. Bjoreman; Regionsjukhuset,

Linköping: C. Malm; Sahlgrenska Hospital, Göteborg: H.
Wadenvik; Endokrinsekt/Medklin
Universitetssjukhuset, Lund: P.-G. Nilsson;
Universitetssjukhuset Malmo University Hospital, Malmo: I.
Turesson. Switzerland — Kantonsspital, St.
Gallen: U. Hess; University of Bern, Bern: M. Solenthaler.
United Kingdom — University of Nottingham and Nottingham
City Hospital, Nottingham:
N. Russell; Kings College, London: G. Mufti; St. George’s
Hospital, Medical School, London: J. Cavenagh; Royal
Liverpool University Hospital, Liverpool:
R.E. Clark; Cambridge Institute for Medical Research,
Cambridge: A.R. Green; Glasgow Royal Infirmary, Glasgow:
T.L. Holyoake; Manchester Royal
Infirmary, Manchester: G.S. Lucas; Leeds General Infirmary,
Leeds: G. Smith; Queen Elizabeth Hospital, Edgbaston,
Birmingham: D.W. Milligan; Der-
riford Hospital, Plymouth: S.J. Rule; University Hospital of
Wales, Cardiff: A.K. Burnett; United States — Walt Disney
Memorial Cancer Institute, Or-
lando, FL: R. Moroose; Roswell Park Cancer Center, Buffalo,
NY: M. Wetzler; Gibbs Cancer Center, Spartanburg, SC: J.
Bearden; Ohio State University
School of Medicine, Columbus: S. Cataland; University of New
Mexico Health Sciences Center, Albuquerque: I. Rabinowitz;
University of Maryland Cancer
Center, Baltimore: B. Meisenberg; Montgomery Cancer Center,
Montgomery, AL: K. Thompson; State University of New York
Upstate Medical Center,
Syracuse: S. Graziano; University of Alabama at Birmingham,
Birmingham: P. Emanuel; Hematology and Oncology, Inc.,
Dayton, OH: H. Gross;
Billings Oncology Associates, Billings, MT: P. Cobb; City of
Hope National Medical Center, Duarte, CA: R. Bhatia; Cancer
Center of Kansas, Wichita: S.
Dakhil; Alta Bates Comprehensive Cancer Center, Berkeley,

CA: D. Irwin; Cancer Research Center of Hawaii, Honolulu: B.
Issell; University of Nebraska
Medical Center, Omaha: S. Pavletic; Columbus Community
Clinical Oncology Program, Columbus, OH: P. Kuebler;
Michigan State University Hematol-
ogy/Oncology, Lansing: E. Layhe; Brown University School of
Medicine, Providence, RI: P. Butera; Loyola University Medical
Center, Shreveport, LA: J.
Glass; Duke University Medical Center, Durham, NC: J. Moore;
University of Vermont, Burlington: B. Grant; University of
Tennessee, Memphis: H. Niell;
University of Louisville Hospital, Louisville, KY: R. Herzig;
Sarah Cannon Cancer Center, Nashville: H. Burris; University
of Minnesota, Minneapolis: B.
Peterson; Cleveland Clinic Foundation, Cleveland: M. Kalaycio;
Fred Hutchinson Cancer Research Center, Seattle: D. Stirewalt;
University of Utah, Salt
Lake City: W. Samlowski; Memorial Sloan-Kettering Cancer
Center, New York: E. Berman; University of North Carolina
School of Medicine, Charlotte: S.
Limentani; Atlanta Cancer Center, Atlanta: T. Seay; University
of North Carolina School of Medicine, Chapel Hill: T. Shea;
Indiana Blood and Marrow
Institute, Beech Grove: L. Akard; San Juan Regional Cancer
Center, Farmington, NM: G. Smith; University of Massachusetts
Memorial Medical Center,
Worcester: P. Becker; Washington University School of
Medicine, St. Louis: S. Devine; Veterans Affairs Medical
Center, Milwaukee: R. Hart; Louisiana
State University Medical Center, New Orleans: R. Veith;
Decatur Memorial Hospital, Decatur, IL: J. Wade; Rocky
Mountain Cancer Centers, Denver: M.
Brunvand; Oncology-Hematology Group of South Florida,
Miami: L. Kalman; Memphis Cancer Center, Memphis, TN: D.
Strickland; Henry Ford Hospi-
tal, Detroit: M. Shurafa; University of California, San Diego,

Medical Center, La Jolla: A. Bashey; Western Pennsylvania
Cancer Institute, Pittsburgh: R.
Shadduck; Tulane Cancer Center, New Orleans: H. Safah;
Southbay Oncology Hematology Partners, Campbell, CA: M.
Rubenstein; University of Texas
Southwest Medical Center, Dallas: R. Collins; Cancer Care
Associates, Tulsa, OK: A. Keller; Robert H. Lurie
Comprehensive Cancer Center, Chicago: M.
Tallman; Northern New Jersey Cancer Center, Hackensack: A.
Pecora; University of Pittsburgh Medical Center, Hillman
Cancer Center, Pittsburgh: M. Agha;
Texas Oncology, Dallas: H. Holmes; and New Mexico Oncology
Hematology Consultants, Albuquerque: R. Guidice. Study
Management Committee:
Oregon Health and Science University Cancer Institute
Research and Patient Care, Portland: B.J. Druker; University
Hospital, Poitier, France: F. Guilhot;
University of Chicago, Chicago: R.A. Larson; University of
Newcastle upon Tyne, Newcastle upon Tyne, UK: S.G. O’Brien.
Independent Data Monitor-
ing Board: Rambam Medical Center, Haifa, Israel: J. Rowe;
Wayne State University, Barbara Ann Karmanos Cancer
Institute, Detroit: C.A. Schiffer;
International Drug Development Institute, Brussels: M. Buyse.
Protocol Working Group: Policlinico San Orsola–Malpighi,
Bologna, Italy: M. Bacca-
rani; Hospital Clinic, Barcelona: F. Cervantes; Erasmus Medical
Center, Rotterdam, the Netherlands: J. Cornelissen; Johannes
Gutenberg Universität,
Mainz, Germany: T. Fischer; Universität Heidelberg,
Mannheim, Germany: A. Hochhaus; Hanson Institute Centre for
Cancer, Adelaide, Australia: T.
Hughes; Medical University of Vienna, Vienna: K. Lechner;
Aarhus Amtssygehus, Aarhus, Denmark: J.L. Nielsen; CHU de
Bordeaux, Pessac, France: J.
Reiffers; Hôpital Saint Louis, Paris: P. Rousselot; San Luigi

Gonzaga Hospital, Turin, Italy: G. Saglio; Vancouver Hospital,
Vancouver, BC, Canada:
J. Shepherd; Akademiska Sjukhuset, Uppsala, Sweden: B.
Simonsson; University Hospital, Basel, Switzerland: A.
Gratwohl; Imperial College,
London: J.M. Goldman; University of Michigan Health System,
Ann Arbor: M. Talpaz; Mater Misericordiae Public Hospital,
Brisbane, Australia: K.
Taylor; and University Hospital Gasthuisberg, Leuven,
Belgium: G. Verhoef.
reserved.
emi a
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29. Kantarjian H, Giles F, Wunderle L, et
al. Nilotinib in imatinib-resistant CML
and Philadelphia chromosome–positive
ALL. N Engl J Med 2006;354:2542-51.
30. Copland M, Hamilton A, Elrick LJ, et

al. Dasatinib (BMS-354825) targets an ear-
lier progenitor population than imatinib
in primary CML but does not eliminate
the quiescent fraction. Blood 2006;107:
4532-9.
31. Shah NP, Sawyers CL. Mechanisms of
resistance to STI571 in Philadelphia chro-
mosome-associated leukemias. Oncogene
2003;22:7389-95.
32. Willis SG, Lange T, Demehri S, et al.
High-sensitivity detection of BCR-ABL ki-
nase domain mutations in imatinib-naive
patients: correlation with clonal cytoge-
netic evolution but not response to thera-
py. Blood 2005;106:2128-37.
33. Roche-Lestienne C, Preudhomme C.
Mutations in the ABL kinase domain pre-
exist the onset of imatinib treatment.
Semin Hematol 2003;40:Suppl 2:80-2.
34. Griswold IJ, MacPartlin M, Bumm T,
et al. Kinase domain mutants of Bcr-Abl
exhibit altered transformation potency,
kinase activity, and substrate utilization,
irrespective of sensitivity to imatinib. Mol
Cell Biol 2006;26:6082-93.
Copyright © 2006 Massachusetts Medical Society.
reserved.
A minimum of 100 words each and References Response (#1 –

6) KEEP RESPONSE WITH ANSWER EACH ANSWER NEED
TO HAVE A SCHOLARY SOURCE with a Hyperlink
Make sure the Responses includes the Following: (a) an
understanding of the weekly content as supported by a scholarly
resource, (b) the provision of a probing question. (c) stay on
topic
1. A categorical approach is an approach that classifies mental
disorders through assessment. Whether an individual may have
the disorder based on symptoms and characteristics, in which
can be described as typical type of disorder. The categorical
approach is classified in two strategies ICD and DSM. ICD
identifies symptoms, that indicate the presence of a disorder.
The DSM names the disorder and defines them in specific terms
(Potuzak et a.l, 2012).
A dimensional approach is an approach that classifies mental
disorders that measures a person’s symptoms. Many other
characteristics of interest are represented with numerical values,
that are measured on one or more scales or continuums and are
not just assigned to a mental disorder category. The dimensional
approach provides detailed information for each symptom, with
a significant number of factors that are taken in to account. I
think this approach is best to classify disorders symptoms are
actually measured. The categorical approach, I think can lead to
misdiagnoses. The reason being is just because symptoms are
displayed does not mean someone has a personality disorder,
there should be more measured research to show what the true
issues are (Comer, 2018) .
2. Both the DSM-5 and the DSM (IV-TR), were created in order
for clinicians to classify and diagnose disorders within an
individual. The DSM(IV-TR) was described as a multiaxial
approach, intended to assist with comprehensive evaluations of
a client’s overall level of functioning (Whitbourne, 2013). This
version derived disorder using five different dimensions, as the
idea was mental illness often can impact one across many
different life areas. The newer DSM-5 essentially eliminated

what was considered a cumbersome five axis diagnostic system;
this included rating each client according to criteria other than
their primary disorder (Whitbourne, 2013). Another positive for
DSM-5 is that it reorganized and eliminated some disorders that
no longer made sense,
Personally, I support he categorical approach as there are more
buckets and ways to look at metal illness across all areas of life.
I also think that it is the best in classifying personality
disorders is the SDM-IV-TR approach. This approach looks at
personality disorders in how an individual relates to the world,
including antisocial and histrionic personality disorders
(Whitbourne, 2013).
3. The dimensional approach of Diagnostic and Statistical
Manual of Mental Disorders (DSM) is better because it gives
the severity of personality traits rather than the presence or
absence of specific traits. People with a personality disorder are
those who display extreme degrees of problematic traits. DSM-5
overlap so much that clinicians often find it difficult to
distinguish one disorder from another, resulting in frequent
disagreements about which diagnosis is correct for a person
with a personality disorder (Comer, 2018). The categorical
model assumes each personality disorder is a separate and
distinct category. For example, separate from other personality
disorders, and distinct from "normal" personalities. The
categorical approach assumes a lot can be wrong or not wrong
with someone, which is why the dimensional approach makes it
more clear. Lets say you have a dog, that dog is a husky, which
is a type of wolf. To further explore the history of this dog, one
has to look into it's traits to see why we have categorized it as a
wolf breed. This is just like the dimensional approach to a
disorder, to see what other reasons someone is or isn't paranoid,
antisocial or has obsessive- compulsive (OCD).
4. Autism spectrum disorder (ASD) is classified as a spectrum
disorder because there is a wide variation of how the disorder
affects people (Comer, 2018) Autism spectrum disorder is a

very hot topic of debate for many individuals and each one has
a differ in opinion on what causes the disorder. However, it is
not really known what causes autism spectrum disorder it is said
that it could be because of genetic factors or even
environmental factors. The symptoms of autism can vary
depending on the individual. I have a nephew who has autism
spectrum disorder and the symptoms that he has are difficulties
being in large rooms of people he doesn’t know, sound
aversions, texture aversions, repetitive aversions, repetitive
behavior, and restricted interests. Trying to find solutions to
make an individual who has autism spectrum disorder life easier
can vary as well. My nephew goes to behavior therapy to help
him learn how to communicate with those around him, and new
people.
5. Autism Spectrum Disorder can present in a variety of
degrees. The most common features are extreme aloofness,
inability to share attention with others, lack of interest in other
people, low empathy levels, poor language skills or failure to
speak, and rigid behaviors, activities, and interests (Comer,
2018). Recent biological and psychological studies point to
cognitive limitations and brain abnormalities as the primary
causes (Comer, 2018). Boys are much more likely than girls to
have ADS and if one sibling has it the chances are around 20%
for other siblings to develop ASD. Cognitive-behavioral
therapy, communication training, and parent training are some
of the treatments for ASD (Comer, 2018). Unfortunately, these
treatments are mostly geared toward skill development because
ADS is generally a life-long condition.
6. Autism spectrum disorder (ASD) is when a child shows signs
of being unresponsive and has trouble communicating with
others. “These symptoms appear early in life, typically around 3
years of age (Comer, 2018).” The symptoms for this disorder
can be different for every child. Some children show symptoms
of being unresponsive in social situations. These children may

lack interest in certain activities and can be hard for them to
give attention to others. “Many people with the disorder have
great difficulty understanding speech or using language for
conversational purposes (Comer, 2018).”
“More recent work in the psychological and biological spheres
has persuaded clinical theorists that cognitive limitations and
brain abnormalities are the primary causes of the disorder
(Comer, 2018).” Theorists look toward these two causes for this
disorder because they explain more about the causes of this
disorder. The psychological cause for this disorder focuses more
on the brain and the way the child is thinking. Most children
develop a way of thinking and reading other people, but
children with ASD have a harder time doing this. The biological
cause focuses more on the genetic standpoint and birth
complications. If a child is born with a certain abnormality
within the brain, this can lead to this disorder.
Some treatments for this disorder would be cognitive-behavioral
therapy, communication training, parent training, and
community integration. These treatments aim to help the child
and the family understand this disorder and learn how to
function everyday. Every treatment focuses on the child and
helps them feel like everybody else and not left out.
Review article
The molecular biology of chronic myeloid leukemia
Michael W. N. Deininger, John M. Goldman, and Junia V. Melo
Chronic myeloid leukemia (CML) is probably the most
extensively
studied human malignancy. The discovery of the Philadelphia
(Ph)
chromosome in 19601 as the first consistent chromosomal
abnormal-

ity associated with a specific type of leukemia was a
breakthrough
in cancer biology. It took 13 years before it was appreciated
that the
Ph chromosome is the result of a t(9;22) reciprocal
chromosomal
translocation2 and another 10 years before the translocation was
shown to involve theABL proto-oncogene normally on chromo-
some 93 and a previously unknown gene on chromosome 22,
later
termedBCR for breakpoint cluster region.4 The deregulated Abl
tyrosine kinase activity was then defined as the pathogenetic
principle,5 and the first animal models were developed.6 The
end of
the millennium sees all this knowledge transferred from the
bench
to the bedside with the arrival of Abl-specific tyrosine kinase
inhibitors that selectively inhibit the growth ofBCR-ABL–
positive
cells in vitro7,8 and in vivo.9
In this review we will try to summarize what is currently known
about the molecular biology of CML. Because several aspects of
CML pathogenesis may be attributable to the altered function of
the
2 genes involved in the Ph translocation, we will also address
the
physiological roles ofBCRandABL. We concede that a review of
this nature can never be totally comprehensive without losing
clarity, and we therefore apologize to any authors whose work
we
have not cited.
The physiologic function
of the translocation partners

The ABL gene is the human homologue of the v-abl oncogene
carried by the Abelson murine leukemia virus (A-MuLV),10 and
it
encodes a nonreceptor tyrosine kinase.11 Human Abl is a
ubiqui-
tously expressed 145-kd protein with 2 isoforms arising from
alternative splicing of the first exon.11 Several structural
domains
can be defined within the protein (Figure 1). Three SRC
homology
domains (SH1-SH3) are located toward the NH2 terminus. The
SH1 domain carries the tyrosine kinase function, whereas the
SH2
and SH3 domains allow for interaction with other proteins.12
Proline-rich sequences in the center of the molecule can, in
turn,
interact with SH3 domains of other proteins, such as Crk.13
Toward
the 39 end, nuclear localization signals14 and the DNA-
binding15
and actin-binding motifs16 are found.
Several fairly diverse functions have been attributed to Abl, and
the emerging picture is complex. Thus, the normal Abl protein
is
involved in the regulation of the cell cycle,17,18 in the cellular
response to genotoxic stress,19 and in the transmission of
informa-
tion about the cellular environment through integrin
signaling.20
(For a comprehensive review of Abl function, see Van Etten21).
Overall, it appears that the Abl protein serves a complex role as

a
cellular module that integrates signals from various
extracellular
and intracellular sources and that influences decisions in regard
to
cell cycle and apoptosis. It must be stressed, however, that
many of
the data are based solely on in vitro studies in fibroblasts, not
hematopoietic cells, and are still controversial. Unfortunately,
the
generation ofABL knockout mice failed to resolve most of the
outstanding issues.22,23
The 160-kd Bcr protein, like Abl, is ubiquitously expressed.11
Several structural motifs can be delineated (Figure 2). The first
N-terminal exon encodes a serine–threonine kinase. The only
substrates of this kinase identified so far are Bap-1, a member
of the
14-3-3 family of proteins,24 and possibly Bcr itself.11 A
coiled–coil
domain at the N-terminus of Bcr allows dimer formation in
vivo.25
The center of the molecule contains a region withdbl-like and
pleckstrin-homology (PH) domains that stimulate the exchange
of
guanidine triphosphate (GTP) for guanidine diphosphate (GDP)
on
Rho guanidine exchange factors,26 which in turn may activate
transcription factors such as NF-kB.27 The C-terminus has
GTPase
activity for Rac,28 a small GTPase of the Ras superfamily that
regulates actin polymerization and the activity of an NADPH
oxidase in phagocytic cells.29 In addition, Bcr can be
phosphory-

lated on several tyrosine residues,30 especially tyrosine 177,
which
binds Grb-2, an important adapter molecule involved in the
activation of the Ras pathway.31 Interestingly, Abl has been
shown
to phosphorylate Bcr in COS1 cells, resulting in a reduction of
Bcr
kinase activity.31,32 Although these data argue for a role of Bcr
in
signal transduction, their true biologic relevance remains to be
determined. The fact thatBCR knockout mice are viable and the
fact that an increased oxidative burst in neutrophils is thus far
the
only recognized defect33 probably reflect the redundancy of
signaling pathways. If there is a role for Bcr in the pathogenesis
of
Ph-positive leukemias, it is not clearly discernible because the
incidence and biology of P190BCR-ABL-induced leukemia are
the
same inBCR2/2 mice as they are in wild-type mice.34
Molecular anatomy
of the BCR-ABL translocation
The breakpoints within theABL gene at 9q34 can occur
anywhere
over a large (greater than 300 kb) area at its 59 end, either
upstream
From the Department of Hematology/Oncology, University of
Leipzig,
Germany; and the Department of Haematology, Imperial
College School of
Medicine, Hammersmith Hospital, London, United Kingdom.
Submitted November 16, 1999; accepted July 12, 2000.

Supported by grants from Leukaemia Research Fund (UK) and
the Dr Ernst
und Anita Bauer Stiftung (Germany).
Reprints: Michael W. N. Deininger, Department of
Hematology/Oncology,
University of Leipzig, Johannisallee 32, Leipzig 04103,
Germany; e-mail:
[email protected]
The publication costs of this article were defrayed in part by
page charge
payment. Therefore, and solely to indicate this fact, this article
is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section
1734.
© 2000 by The American Society of Hematology
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of the first alternative exon Ib, downstream of the second
alterna-
tive exon Ia, or, more frequently, between the two35 (Figure 3).
Regardless of the exact location of the breakpoint, splicing of
the
primary hybrid transcript yields an mRNA molecule in
whichBCR
sequences are fused toABL exon a2. In contrast toABL, break-
points within BCR localize to 1 of 3 so-called breakpoint
cluster
regions (bcr). In most patients with CML and in approximately
one
third of patients with Ph-positive acute lymphoblastic leukemia
(ALL), the break occurs within a 5.8-kb area
spanningBCRexons
12-16 (originally referred to as exons b1-b5), defined as the
major
breakpoint cluster region (M-bcr). Because of alternative
splicing,
fusion transcripts with either b2a2 or b3a2 junctions can be
formed.
A 210-kd chimeric protein (P210BCR-ABL) is derived from this
mRNA. In the remaining patients with ALL and rarely in
patients
with CML, characterized clinically by prominent
monocytosis,36,37
the breakpoints are further upstream in the 54.4-kb region
between
the alternativeBCRexons e29 and e2, termed the minor
breakpoint
cluster region (m-bcr). The resultant e1a2 mRNA is translated
into
a 190-kd protein (P190BCR-ABL). Recently, a third breakpoint
cluster
region (m-bcr) was identified downstream of exon 19, giving

rise to
a 230-kd fusion protein (P230BCR-ABL) associated with the
rare
Ph-positive chronic neutrophilic leukemia,38 though not in all
cases.39 If sensitive techniques such as nested reverse
transcription–
polymerase chain reaction are used, transcripts with the e1a2
fusion
are detectable in many patients with classical P210BCR-
ABLCML.40
The low level of expression of these P190-type transcripts com-
pared to P210 indicates that they are most likely the result of
alternative splicing of the primary mRNA. Occasional cases
with
other junctions, such as b2a3, b3a3, e1a3, e6a2,41 or e2a2,42
have
been reported in patients with ALL and CML. These
“experiments
of nature” provide important information as to the function of
the
various parts ofBCR and ABL in the oncogenic fusion protein.
Interestingly,ABL exon 1, even if retained in the genomic
fusion, is
never part of the chimeric mRNA. Thus, it must be spliced out
during processing of the primary mRNA; the mechanism
underly-
ing this apparent peculiarity is unknown. Based on the
observation
that the Abl part in the chimeric protein is almost invariably
constant while the Bcr portion varies greatly, one may deduce
that
Abl is likely to carry the transforming principle whereas the
different sizes of the Bcr sequence may dictate the phenotype of
the

disease. In support of this notion, rare cases of ALL express a
TEL-ABL fusion gene,43,44 indicating that theBCR moiety can
in
principle be replaced by other sequences and still cause
leukemia.
Interestingly, a fusion betweenTEL(ETV6) and theABL-related
geneARG has recently been described in a patient with AML.45
Although all 3 major Bcr-Abl fusion proteins induce a CML-
like
disease in mice, they differ in their ability to induce lymphoid
leukemia,46 and, in contrast to P190 and P210, transformation
to
growth factor independence by P230BCR-ABL is incomplete,47
which
is consistent with the relatively benign clinical course of P230-
positive chronic neutrophilic leukemia.38
One of the most intriguing questions relates to the events
responsible for the chromosomal translocation in the first place.
From epidemiologic studies it is well known that exposure to
ionizing radiation (IR) is a risk factor for CML.48,49 Moreover,
BCR-ABLfusion transcripts can be induced in hematopoietic
cells
by exposure to IR in vitro50; such IR-induced translocations
may
not be random events but may depend on the cellular
background
and on the particular genes involved. Two recent reports showed
that the physical distance between theBCR and theABL genes in
human lymphocytes51 and CD341 cells52 is shorter than might
be
expected by chance; such physical proximity could favor
transloca-
tion events involving the 2 genes. However, the presence of the
BCR-ABL translocation in a hematopoietic cell is not in itself

sufficient to cause leukemia becauseBCR-ABLfusion transcripts
of
M-bcr and m-bcr type are detectable at low frequency in the
blood
of many healthy individuals.53,54 It is unclear why Ph-positive
leukemia develops in a tiny minority of these persons. It may be
that the translocation occurs in cells committed to terminal
differentiation that are thus eliminated or that an immune
response
suppresses or eliminates Bcr-Abl–expressing cells. Indirect evi-
dence that such a mechanism may be relevant comes from the
observation that certain HLA types protect against CML.55
Another
possibility is thatBCR-ABLis not the only genetic lesion
required
to induce chronic-phase CML. Indeed, a skewed pattern of G-
6PD
Figure 1. Structure of the Abl protein. Type Ia isoform is
slightly shorter than type
Ib, which contains a myristoylation (myr) site for attachment to
the plasma mem-
brane. Note the 3 SRC-homology (SH) domains situated toward
the NH2 terminus.
Y393 is the major site of autophosphorylation within the kinase
domain, and
phenylalanine 401 (F401) is highly conserved in PTKs
containing SH3 domains. The
middle of each protein is dominated by proline-rich regions
(PxxP) capable of binding
to SH3 domains, and it harbors 1 of 3 nuclear localization
signals (NLS). The carboxy
terminus contains DNA as well as G- and F-actin–binding
domains. Phosphorylation
sites by Atm, cdc2, and PKC are shown. The arrowhead
indicates the position of the

breakpoint in the Bcr-Abl fusion protein.
Figure 2. Structure of the Bcr protein. Note the dimerization
domain (DD) and the 2
cyclic adenosine monophosphate kinase homologous domains at
the N terminus.
Y177 is the autophosphorylation site crucial for binding to Grb-
2. The center of the
molecule contains a region homologous to Rho guanidine
nucleotide exchange
factors (Rho-GEF) as well as dbl-like and pleckstrin homology
(PH) domains. Toward
the C-terminus a putative site for calcium-dependent lipid
binding (CaLB) and a
domain with activating function for Rac-GTPase (Rac-GAP) are
found. Arrowheads
indicate the position of the breakpoints in the BCR-ABL fusion
proteins.
Figure 3. Locations of the breakpoints in the ABL and BCR
genes and structure
of the chimeric mRNAs derived from the various breaks.
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isoenzymes has been detected in Ph-negative Epstein-Barr
virus-
transformed B-cell lines derived from patients with CML,
suggest-
ing that a Ph-negative pathologic state may precede the
emergence
of the Ph chromosome.56
Mechanisms of BCR-ABL –mediated
malignant transformation
Essential features of the Bcr-Abl protein
Mutational analysis identified several features in the chimeric
protein that are essential for cellular transformation (Figure 4).
In
Abl they include the SH1, SH2, and actin-binding domains
(Figure
1), and in Bcr they include a coiled–coil motif contained in
amino
acids 1-63,25 the tyrosine at position 177,57 and
phosphoserine–
threonine-rich sequences between amino acids 192-242 and 298-
41358 (Figure 2). It is, however, important to note that essential
features depend on the experimental system. For example, SH2
deletion mutants of Bcr-Abl are defective for fibroblast
transforma-
tion,59 but they retain the capacity to transform cell lines to
factor
independence and are leukemogenic in animals.60
Deregulation of the Abl tyrosine kinase
Abl tyrosine kinase activity is tightly regulated under physi-
ologic conditions. The SH3 domain appears to play a critical

role in this inhibitory process because its deletion14 or
positional
alteration61 activates the kinase; it is replaced by viralgag
sequences in v-abl.62 Both cis- and trans-acting mechanisms
have been proposed to mediate the repression of the kinase.
Several proteins have been identified that bind to the SH3
domain.63-65 Abi-1 and Abi-2 (Abl interactor proteins 1 and 2)
activate the inhibitory function of the SH3 domain; even more
interesting, activated Abl proteins promote the proteasome-
mediated degradation of Abi-166 and Abi-2. Another candidate
inhibitor of Abl is Pag/Msp23. On exposure of cells to oxidative
stress such as ionizing radiation, this small protein is oxidized
and dissociates from Abl, whose kinase is in turn activated.67
These results are in line with previous observations that highly
purified Abl protein is kinase-active,61 suggesting that its
constitutive inhibition derives from a trans-acting mechanism.
Alternatively, the SH3 domain may bind internally to the
proline-rich region in the center of the Abl protein, causing a
conformational change that inhibits interaction with sub-
strates.68 Furthermore, a mutation of Phe401 to Val (within the
kinase domain) leads to the transformation of rodent fibroblasts.
Because this residue is highly conserved in tyrosine kinases
with
N-terminal SH3 domains, it may bind internally to the SH3
domain.69 It is conceivable that the fusion of Bcr sequences 59
of
the Abl SH3 domain abrogates the physiologic suppression of
the kinase. This might be the consequence of homodimer
formation; indeed, the N-terminal dimerization domain is an
essential feature of the Bcr-Abl protein but can be functionally
replaced by other sequences that allow for dimer formation,
such as the N-terminus of theTEL (ETV-6) transcription factor
in the TEL-ABL fusion associated with the t(9;12).43,70 It is
possible that deregulated tyrosine kinase activity is a unifying

feature of chronic myeloproliferative disorders. Several other
reciprocal translocations have been cloned from patients with
chronic BCR-ABL–negative myeloproliferative disorders. Re-
markably, most of these turn out to involve tyrosine kinases
such
as fibroblast growth factor receptor 171 and platelet-derived
growth factorb receptor (PDGFbR).72
A host of substrates can be tyrosine phosphorylated byBcr-Abl
(Table 1). Most important, because of autophosphorylation,
there is
a marked increase of phosphotyrosine onBcr-Abl itself, which
creates binding sites for the SH2 domains of other proteins.
Generally, substrates ofBcr-Abl can be grouped according to
their
physiologic role into adapter molecules (such as Crkl and
p62DOK),
proteins associated with the organization of the cytoskeleton
and
the cell membrane (such as paxillin and talin), and proteins with
catalytic function (such as the nonreceptor tyrosine kinase Fes
or
the phosphatase Syp). It is important to note that the choice of
substrates depends on the cellular context. For example, Crkl is
the
major tyrosine-phosphorylated protein in CML neutrophils,73
whereas phosphorylated p62DOK is predominantly found in
early
progenitor cells.74
Tyrosine phosphatases counterbalance and regulate the effects
of tyrosine kinases under physiologic conditions, keeping
cellular
phosphotyrosine levels low. Two tyrosine phosphatases, Syp83
and

PTP1B,84 have been shown to form complexes with Bcr-Abl,
and
both appear to dephosphorylate Bcr-Abl. Interestingly, PTP1B
levels increase in a kinase-dependent manner, suggesting that
the
cell attempts to limit the impact of Bcr-Abl tyrosine kinase
activity.
At least in fibroblasts, transformation by Bcr-Abl is impaired by
the
overexpression of PTP1B.85 Interestingly, we recently observed
the
up-regulation of receptor protein tyrosine phosphatasek (RPTP-
k)
with the inhibition of Bcr-Abl in BV173 cells treated with the
Figure 4. Signaling pathways activated in BCR-ABL –positive
cells. Note that this
is a simplified diagram and that many more associations
between Bcr-Abl and
signaling proteins have been reported.
Table 1. Substrates of BCR-ABL
Protein Function Reference
P62DOK Adapter 74
Crkl Adapter 73
Crk Adapter 13
Shc Adapter 75
Talin Cytoskeleton/cell membrane 76
Paxillin Cytoskeleton/cell membrane 77

Fak Cytoskeleton/cell membrane 78
Fes Myeloid differentiation 79
Ras-GAP Ras-GTPase 80
GAP-associated proteins Ras activation? 214
PLCg Phospholipase 80
PI3 kinase (p85 subunit) Serine kinase 127
Syp Cytoplasmic phosphatase 83
Bap-1 14-3-3 protein 24
Cbl Unknown 81
Vav Hematopoietic differentiation 82
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tyrosine kinase inhibitor STI571,86 which suggests that the

oppo-
site effect may also occur. Thus, though the pivotal role of Bcr-
Abl
tyrosine kinase activity is clearly established, much remains to
be
learned about the significance of tyrosine phosphatases in the
transformation process.
Activated signaling pathways and biologic properties
of BCR-ABL–positive cells
Three major mechanisms have been implicated in the malignant
transformation byBcr-Abl, namely altered adhesion to stroma
cells
and extracellular matrix,87 constitutively active mitogenic
signal-
ing88 and reduced apoptosis89 (Figure 5). A fourth possible
mechanism is the recently described proteasome-mediated
degrada-
tion of Abl inhibitory proteins.66
Altered adhesion properties
CML progenitor cells exhibit decreased adhesion to bone
marrow stroma cells and extracellular matrix.87,90 In this sce-
nario, adhesion to stroma negatively regulates cell proliferation,
and CML cells escape this regulation by virtue of their
perturbed
adhesion properties. Interferon-a (IFN-a), an active therapeutic
agent in CML, appears to reverse the adhesion defect.91 Recent
data suggest an important role forb-integrins in the interaction
between stroma and progenitor cells. CML cells express an
adhesion-inhibitory variant ofb1 integrin that is not found in
normal progenitors.92 On binding to their receptors, integrins
are
capable of initiating normal signal transduction from outside to

inside93; it is thus conceivable that the transfer of signals that
normally inhibit proliferation is impaired in CML cells. Because
Abl has been implicated in the intracellular transduction of such
signals, this process may be further disturbed by the presence of
a large pool of Bcr-Abl protein in the cytoplasm. Furthermore,
Crkl, one of the most prominent tyrosine-phosphorylated pro-
teins in Bcr-Abl–transformed cells,73 is involved in the regula-
tion of cellular motility94 and in integrin-mediated cell adhe-
sion95 by association with other focal adhesion proteins such as
paxillin, the focal adhesion kinase Fak, p130Cas,96 and Hef1.97
We recently demonstrated that Bcr-Abl tyrosine kinase up-
regulates the expression ofa6 integrin mRNA,86 which points to
transcriptional activation as yet another possible mechanism by
which Bcr-Abl may have an impact on integrin signaling. Thus,
though there is sound evidence that Bcr-Abl influences integrin
function, it is more difficult to determine the precise nature of
the biologic consequences, and, at least in certain cellular
systems, integrin function appears to be enhanced rather than
reduced by Bcr-Abl.98
Activation of mitogenic signaling
Ras and the MAP kinase pathways.Several links between
Bcr-Abl and Ras have been defined. Autophosphorylation of
tyrosine 177 provides a docking site for the adapter molecule
Grb-2.57 Grb-2, after binding to the Sos protein, stabilizes Ras
in its
active GTP-bound form. Two other adapter molecules, Shc and
Crkl, can also activate Ras. Both are substrates of Bcr-Abl73,99
and
bind Bcr-Abl through their SH2 (Shc) or SH3 (Crkl) domains.
The
relevance of Ras activation by Crkl is, however, questionable
because it appears to be restricted to fibroblasts.100 Moreover,
direct

binding of Crkl to Bcr-Abl is not required for the
transformation of
myeloid cells.101 Circumstantial evidence that Ras activation is
important for the pathogenesis of Ph-positive leukemias comes
from the observation that activating mutations are uncommon,
even
in the blastic phase of the disease,102 unlike in most other
tumors.
This implies that the Ras pathway is constitutively active, and
no
further activating mutations are required. There is still dispute
as to
which mitogen-activated protein (MAP) kinase pathway is
down-
stream of Ras in Ph-positive cells. Stimulation of cytokine
receptors such as IL-3 leads to the activation of Ras and the
subsequent recruitment of the serine–threonine kinase Raf to the
cell membrane.103 Raf initiates a signaling cascade through the
serine–threonine kinases Mek1/Mek2 and Erk, which ultimately
leads to the activation of gene transcription.104 Although some
data
indicate that this pathway may be activated only in v-abl– but
not in
BCR-ABL–transformed cells,105 this view has recently been
chal-
lenged.106 Moreover, activation of the Jnk/Sapk pathway by
Bcr-Abl has been demonstrated and is required for malignant
transformation107; thus, signaling from Ras may be relayed
through
the GTP–GDP exchange factor Rac108 to Gckr (germinal center
kinase related)109 and further down to Jnk/Sapk (Figure 6).
There is
also some evidence that p38, the third pillar of the MAP kinase
pathway, is also activated in BCR-ABL–transformed cells, and
there are other pathways with mitogenic potential. In any case,
the

signal is eventually transduced to the transcriptional machinery
of
the cell.
It is also possible that Bcr-Abl uses growth factor pathways in a
more direct way. For example, association with thebc subunit of
the IL-3 receptor110 and the Kit receptor111 has been observed.
Interestingly, the pattern of tyrosine-phosphorylated proteins
seenFigure 5. Mechanisms implicated in the pathogenesis of
CML.
Figure 6. Signaling pathways with mitogenic potential in BCR-
ABL –trans-
formed cells. The activation of individual paths depends on the
cell type, but the
MAP kinase system appears to play a central role. Activation of
p38 has been
demonstrated only in v-abl–transformed cells, whereas data for
BCR-ABL–
expressing cells are missing.
3346 DEININGER et al BLOOD, 15 NOVEMBER 2000 z
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in normal progenitor cells after stimulation with Kit ligand is

similar to the pattern seen in CML progenitor cells.112 Dok-1
(p62DOK), one of the most prominent phosphoproteins in this
setting, forms complexes with Crkl, RasGAP, and Bcr-Abl. In
fact,
there may be a whole family of related proteins with similar
functions—for example, the recently described Dok-2
(p56DOK2).113
Somewhat surprisingly, p62DOK is essential for transformation
of
Rat-1 fibroblasts but not for growth-factor independence of my-
eloid cells114; thus, its true role remains to be defined.
Jak-Stat pathway.The first evidence for involvement of the Jak-
Stat pathway came from studies in v-abl–transformed B cells.62
Consti-
tutive phosphorylation of Stat transcription factors (Stat1 and
Stat5) has
since been reported in several BCR-ABL–positive cell lines115
and in
primary CML cells,116 and Stat5 activation appears to
contribute to
malignant transformation.117Although Stat5 has pleiotropic
physiologic
functions,118 its effect in BCR-ABL–transformed cells appears
to be
primarily anti-apoptotic and involves transcriptional activation
of
Bcl-xL.119,120 In contrast to the activation of the Jak-Stat
pathway by
physiologic stimuli, Bcr-Abl may directly activate Stat1 and
Stat5
without prior phosphorylation of Jak proteins. There seems to
be
specificity for Stat6 activation by P190BCR-ABL proteins as
opposed to

P210BCR-ABL.115 It is tempting to speculate that the
predominantly
lymphoblastic phenotype in these leukemias is related to this
peculiarity.
The role of the Ras and Jak-Stat pathways in the cellular
response to growth factors could explain the observation that
BCR-ABLrenders a number of growth factor–dependent cell
lines
factor independent.105,121 In some experimental systems there
is
evidence for an autocrine loop dependent on the Bcr-Abl–
induced
secretion of growth factors,122 and it was recently reported that
Bcr-Abl induces an IL-3 and G-CSF autocrine loop in early
progenitor cells.123 Interestingly, Bcr-Abl tyrosine kinase
activity
may induce expression not only of cytokines but also of growth
factor receptors such as the oncostatin Mb receptor.86 One
should
bear in mind, however, that during the chronic phase, CML
progenitor cells are still dependent on external growth factors
for
their survival and proliferation,124 though less than normal
progeni-
tors.125 A recent study sheds fresh light on this issue.
FDCPmix
cells transduced with a temperature-sensitive mutant ofBCR-
ABL
have a reduced requirement for growth factors at the kinase
permissive temperature without differentiation block.126 This
situa-
tion resembles chronic-phase CML, in which the malignant
clone
has a subtle growth advantage while retaining almost normal
differentiation capacity.

PI3 kinase pathway.PI3 kinase activity is required for the
proliferation of BCR-ABL–positive cells.127 Bcr-Abl forms
multi-
meric complexes with PI3 kinase, Cbl, and the adapter
molecules
Crk and Crkl,95 in which PI3 kinase is activated. The next
relevant
substrate in this cascade appears to be the serine–threonine
kinase
Akt.128 This kinase had previously been implicated in anti-
apoptotic signaling.129 A recent report placed Akt in the down-
stream cascade of the IL-3 receptor and identified the pro-
apoptotic
protein Bad as a key substrate of Akt.130 Phosphorylated Bad is
inactive because it is no longer able to bind anti-apoptotic
proteins
such as BclXL and it is trapped by cytoplasmic 14-3-3 proteins.
Altogether this indicates that Bcr-Abl might be able to mimic
the
physiologic IL-3 survival signal in a PI3 kinase-dependent
manner
(see also below). Ship131 and Ship-2,132 2 inositol
phosphatases
with somewhat different specificities, are activated in response
to
growth factor signals and by Bcr-Abl. Thus, Bcr-Abl appears to
have a profound effect on phosphoinositol metabolism, which
might again shift the balance to a pattern similar to physiologic
growth factor stimulation.
Myc pathway. Overexpression of Myc has been demonstrated
in many human malignancies. It is thought to act as a
transcription
factor, though its target genes are largely unknown. Activation
of

Myc by Bcr-Abl is dependent on the SH2 domain, and the
overexpression of Myc partially rescues transformation-
defective
SH2 deletion mutants whereas the overexpression of a
dominant-
negative mutant suppresses transformation.133 The pathway
linking
Myc to the SH2 domain of Bcr-Abl is still unknown. However,
results obtained in v-abl–transformed cells suggest that the
signal is
transduced through Ras/Raf, cyclin-dependent kinases (cdks),
and
E2F transcription factors that ultimately activate the MYC pro-
moter.134 Similar results were reported for BCR-ABL–
transformed
murine myeloid cells.135 How these findings relate to human
Ph-positive cells is unknown. It seems likely that the effects of
Myc
in Ph-positive cells are probably not different from those in
other
tumors. Depending on the cellular context, Myc may constitute
a
proliferative or an apoptotic signal.136,137It is therefore likely
that
the apoptotic arm of its dual function is counterbalanced in
CML
cells by other mechanisms, such as the PI3 kinase pathway.
Inhibition of apoptosis
Expression of Bcr-Abl in factor-dependent murine138 and
human122 cell lines prevents apoptosis after growth-factor
with-
drawal, an effect that is critically dependent on tyrosine kinase
activity and that correlates with the activation of Ras.88,139
More-

over, several studies showed thatBCR-ABL–positive cell lines
are
resistant to apoptosis induced by DNA damage.89,140 The
underly-
ing biologic mechanisms are still not well understood. Bcr-Abl
may block the release of cytochrome C from the mitochondria
and
thus the activation of caspases.141,142 This effect upstream of
caspase activation might be mediated by the Bcl-2 family of
proteins. Bcr-Abl has been shown to up-regulate Bcl-2 in a Ras-
143
or a PI3 kinase-dependent128 manner in Baf/3 and 32D cells,
respectively. Moreover, as mentioned previously, BclxL is
transcrip-
tionally activated by Stat5 inBCR-ABL–positive cells.119,120
Another link betweenBCR-ABLand the inhibition of apoptosis
might be the phosphorylation of the pro-apoptotic protein Bad.
In
addition to Akt, Raf-1, immediately downstream of Ras,
phosphor-
ylates Bad on 2 serine residues.144,145Two recent studies
provided
evidence that the survival signal provided by Bcr-Abl is at least
partially mediated by Bad and requires targeting of Raf-1 to the
mitochondria.146,147It is also possible that Bcr-Abl inhibits
apopto-
sis by down-regulating interferon consensus sequence binding
protein (ICSBP).148,149 These data are interesting because
ICSBP
knockout mice develop a myeloproliferative syndrome,150 and
hematopoietic progenitor cells from ICSBP2/2 mice show
altered
responses to cytokines.151 The connection to interferona, an
active

agent in the treatment of CML, is obvious.
It becomes clear that the multiple signals initiated by Bcr-Abl
have proliferative and anti-apoptotic qualities that are
frequently
difficult to separate. Thus, Bcr-Abl may shift the balance
toward
the inhibition of apoptosis while simultaneously providing a
proliferative stimulus. This is in line with the concept that a
proliferative signal leads to apoptosis unless it is
counterbalanced
by an anti-apoptotic signal,152 and Bcr-Abl fulfills both
require-
ments at the same time. There is, however, controversy. One
report
found 32D cells transfected withBCR-ABLto be more sensitive
to
IR than the parental cells,153 whereas 2 other studies failed to
detect
any difference between CML and normal primary progenitor
cells
with regard to their sensitivity to IR and growth factor with-
drawal.124,154Furthermore, based on results obtained in
transfected
cell systems, it was suggested that Bcr-Abl inhibits apoptosis
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mediated by the Fas receptor/Fas ligand system.155 However,
though there may be a role for this system in mediating the
clinical
response to interferon-a,156 there is no indication that Fas-
triggered
apoptosis is defective in primary CML cells or in “natural”
Ph-positive cell lines.157 Moreover, Bcr-Abl accelerates C2
cer-
amide-induced apoptosis,158 and it does not protect against
natural
killer cell-induced apoptosis.159 These inconsistencies may
reflect
genuine differences between cell lines and primary cells. On the
other hand, it is debatable whether complete growth-factor with-
drawal and IR constitute stimuli that have much physiologic
relevance. To allow for a representative comparison, it would be
crucial to define the signals that induce apoptosis in vivo.
Degradation of inhibitory proteins.
The recent discovery that Bcr-Abl induces the proteasome-
mediated degradation of Abi-1 and Abi-2,66 2 proteins with
inhibitory function, may be the first indication of yet another
way
by which Bcr-Abl induces cellular transformation. Most
compel-
ling, the degradation of Abi-1 and Abi-2 is specific for Ph-
positive
acute leukemias and is not seen in Ph-negative samples of
comparable phenotype. The overall significance of this
observation
remains to be seen, and one must bear in mind that the data

refer to
acute leukemias and not to chronic phase CML. It is
nevertheless
tempting to speculate that other proteins, whose level of
expression
is regulated through the proteasome pathway, may also be de-
graded. A good candidate would be the cell cycle inhibitor p27,
but
to our knowledge no data are available yet.
Experimental models of CML
Various experimental systems have been developed to study the
pathophysiology of CML. All of them have their advantages and
shortcomings, and it is probably fair to say that there is still no
ideal
in vitro or in vivo model that would cover all aspects of the
human disease.
Cell lines
Fibroblasts. Fibroblast lines have been used extensively in CML
research because they are easy to manipulate. Fibroblast
transforma-
tion—that is, anchorage-independent growth in soft agar—is the
standard in vitro test for tumorigenicity.160 However, it became
clear that the introduction ofBCR-ABLinto fibroblasts has
diverse
effects, depending on the type of fibroblast used. Thus, though
P210BCR-ABL transforms Rat-1 fibroblasts,161 there is no
such effect
in NIH3T3.162 Moreover, transformation to serum-independent
growth occurs only in few cells (permissive cells163), whereas
most
undergo growth arrest. These observations show that certain
cellular requirements must be met if a cell is to be transformed

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