More Related Content Similar to Cytogenetics in Chronic myeloid leukaemia (20) Cytogenetics in Chronic myeloid leukaemia4. Differential Diagnosis
Leukemoid reaction
Juvenile myelomonocytic leukemia
Chronic myelomonocytic leukemia
"Atypical CML"
Chronic eosinophilic leukemia
Chronic neutrophilic leukemia
Other myeloproliferative neoplasms
Other Philadelphia chromosome-positive malignancies
6. Molecular basics of CML
• Abelson tyrosine kinase (ABL1)
fusion ABL1 gene
breakpoint cluster region (BCR) gene
BCR-ABL1 –
p210BCR-ABL1
Constitutive
Tyrosine Kinase
activity
-Excessive
Proliferation
-ReducedApoptosis
8. • Minor BCR region (m BCR Region)
• Micro – BCR (µ - BCR)
m BCR p190BCR-ABL1 PredictsWorse outcome
Juxtaposes larger
BCR fragment to
ABL1
p230BCR-ABL1 a/w More Indolent
Course
10. Activated BCR-ABL1
Auto-phosphorylation & Activation of Downstream pathways-
modify – Gene transcription – Apoptosis, - Skeletal
organisations & - Degradation of Inhibitory proteins.
May involve – RAS, Mitogen Activating Protein (MAP) Kinases,
Signal transducers & Activators ofTranscription (STAT),
Phosphatidyl-Inositol -3-Kinase(PI3K),MYC , etc.
11. Binding of BCR-ABL1 to Adapter Protein – GRB-2, CRK, CRK-Like
Protein, SHC (Src homology containing Protein).
BCR-ABL1 TKIs bind to BCR-ABL1 Kinase Domain (KD) – Preventing
Activation ofTransformation pathways & Inhibiting Downstream
signalling.
Plethora of Signalling pathways have been implicated in BCR-ABL1
mediated cellular transformations. – COMPLEX & REDUNDANT
TRANSFORMATION NETWORK.
Differences in SignalTransduction between CML Differentiated Cells &
Early progenitors. Beta-Catenin, Wnt1, Foxo3a,TGF-β, IL-6, PP2A,
SIRT1, - Have been implicated in Stem Cell Survival.
16. Study Calculation Risk definition by calculation
Sokal et al – 1984 Exp. 0.0116 × (Age in Yrs – 43.4) +
(Spleen – 7.51) + 0.188 × [(Platelet
count / 700)2 - 0.563] + 0.0887 ×
(blast cells – 2.10)
Low - <0.8
Intermediate – 0.8 – 1.2
High - >1.2
Hasford et al, 1998 0.666 when Age ≥50 years + (0.042
× Spleen) + 1.0956 when PLT >1500
× 109/L + (0.0584 × Blasts cells) +
0.20399 when Basophils >3% +
(0.0413 × Eosinophils) × 100
Low - ≤ 780
Intermediate - 781 – 1480
High - >1480
EUTOS score - Probability of the patient NOT
to be in CCgR after 18 months of Imatinib therapy.
7 × Basophils + 4 × Spleen size Low risk - ≤ 87
High risk - >87
ELTS score – EUTOS Long term
survival score
0.0025 x (age in completed
years/10)3 + 0.0615 x spleen size
below costal margin + 0.1052 x
blasts in peripheral blood + 0.4104 x
(platelet count/1000)-0.5
Low - ≤ 1.5680
Intermediate - > 1.5680 but ≤
2.2185
High - > 2.2185
21. Mutation imatinib Dasatinib Nilotinib Bosutinib Ponatinib
BCR-ABL1 Confers Confers Confers Confers Confers
BCR-ABL1 c.757T>C (Y253 H) Reduced Retains Reduced ? ?
BCR-ABL1 c.763 G>A (E255K) Reduced Retains Reduced ? ?
BCR-ABL1 c.764 A>T (E255V) Reduced Retains Reduced ? ?
BCR-ABL1 c.895 G>C (V299L) Reduced Reduced Retains ? ?
BCR-ABL1 c.895 G>T (V299L) Reduced Reduced Retains ? ?
BCR-ABL1 c.943 A>G (T315A) Reduced Reduced Retains ? ?
BCR-ABL1 c.944 C>T (T315I) *** Reduced Reduced Reduced Reduced Retains
BCR-ABL1 c.950T>G (F317C) Reduced Reduced Retains ? ?
BCR-ABL1 c.949T>A(F317I) Reduced Reduced Retains ? ?
BCR-ABL1 c.951 C>A (F317L) Reduced Reduced Retains ? ?
BCR-ABL1 c.949T>C (F317L ) Reduced Reduced Retains ? ?
BCR-ABL1 c.951 C>G (F317L) Reduced Reduced Retains ? ?
BCR-ABL1 c.949T>G (F317V) Reduced Reduced Retains ? ?
BCR-ABL1 c.1076T>G (F359C) Reduced Retains Reduced ? ?
BCR-ABL1 c.1075T>A (F359I) Reduced Retains Reduced ? ?
BCR-ABL1 c.1075T>G (F359V) Reduced Retains Reduced ? ?
22. Other
BCR-ABL1
Mutations in
CML
Properties
Mutation Frequency of
Mutation in ABL1-
mutated CML
(COSMIC)
Exon Amino Acid Change Nucleotide Change(s)
4 M244V c.730A>G 7.4%
L248V c.742C>G 2.4%
G250E c.749G>A 10.4%
Q252H c.756G>T
c.756G>C
2.9%
Y253F c.758A>T 1.8%
5 D276G c.827A>G 1.4%
E279K c.835G>A 0.3%
6 F311L c.931T>C
c.933C>A
c.933C>G
0.6%
M351T c.1052T>C 9.0%
E355G c.1064A>G 3.1%
7 V379I c.1135G>A 0.6%
L384M c.1150C>A 0.6%
L387M c.1159T>A 0.8%
H396P c.1187A>C 0.1%
H396R c.1187A>G 3.1%
8 E459K c.1375G>A 1.9%
9 F486S c.1457T>C 1.1%
Implications for targeted therapies
- UNKNOWN