The document examines the aetiology and epidemiology of haematological malignancies, highlighting various causative factors including ionising radiation, chemicals, viruses, and genetic alterations. It discusses the impact of environmental exposures, therapeutic agents, and inherited genetic conditions on the development of these malignancies. Additionally, it details the molecular mechanisms behind malignancy, such as chromosomal translocations, point mutations, and the role of oncogenes and tumor suppressor genes.

1. Haematological Malignancy
BY
ARUOMAREN AUSTIN IROGHAMA

2. Aetiology

3. Epidemiological studies
• Large scale cause and effect studies – MRC -
difficult to conduct due to variety of possible
contributory factors : environmental, socio-
economic conditions and healthcare issues
• Number of patient years required for a conclusion
• A number of factors are considered to be
involved /causative in the aetiology of
haematological malignancies

4. Epidemiological studies

5. Ionising Radiation
• Atom bombs : Hiroshima and Nagasaki –
proven correlation between exposure to
radiation and carcinogenesis incidence CML,
ALL, AML and MM noted in survivors in short
and long term follow-up studies
• Risk of developing leukaemia – inversely related
to distance from hypocentre of explosion

6. Ionising Radiation
Nuclear power stations & reprocessing plants
• Interest focussed on Sellafield reprocessing
plant (1984 govt. enquiry) re. childhood ALL
cluster among those born in the area – not new
comers.
• link with fathers working in the industry – not
conclusive. Is this circumstantial as children of
survivors of Hiroshima have no increased risk

7. Environmental background radiation
• X-Rays : exposure to therapeutic X rays =
increased incidence of leukaemia and solid
tumours.
• Risk of leukaemogenisis increases if alkylating
agents used concurrently
• Prior to protective shielding for staff in X ray
depts (1940) increases leukaemia
• Exposure of foetuses to X ray in 1st trimester
increases incidence ALL

8. Environmental background radiation
• DOH study 2001 : Ionising Radiation and
Medical Reporting (IRMER) – clamp down on
unnecessary exposure – some X rays =radio-
intense
• Therapeutic radiotherapy :combined modality
treatment for HD – 30 fold in developing
leukaemia
• Radiotherapy of Ankylosing Spondilytis
patients correlates with leukamia

9. Chemicals
• Benzene + other petroleum derivatives – BM
hypoplasia, dysplasia, chromosomal abnormalities,
MDS and AML
• Armament waste : unusually high incidence of AML
and CML in Stadtallendorf in Germany –
environmental contamination with TNT (toluene
derivative – similar to benzene)
• Cigarettes: slight increase risk of AML due to
aromatic compounds in smoke
• Agricultural and rubber industry workers -
circumstantial links

10. Therapeutic drugs
• Alkylating agents = radiomimetic drugs ie. melphalan,
azothioprine, chlorambucil, nitosureas (BCNU), nitrogen
mustard - particularly if combined with radiotherapy
assoc. with 2o
AML
• Busulphan prevents DNA strands parting normally –
induces breaks/damage assoc. with lung & ovarian Ca
– Risks increase with exposure - linked with chromosomal
abnormalities
– Development of AML in RhA patients
• Epidophyllotoxins ie etoposide = powerful anti-
leukaemic agent but associated with AML after a latency
period of 1-5 years particularly M4 or M5 and 11q23
mutation

11. Viruses
• Considerable evidence for viral induction of leukaemia
• Oncogenic viruses
– either DNA viruses incl. adenoviruses, herpes viruses
– or RNA viruses including retroviruses
• Viruses are oncogenic via 3 mechanisms :
– Retrovirus contains an oncogene which it inserts into host
genome :RAPID TUMOUR DEVELOPMENT
– Insertion of viral DNA at a specific point in host DNA which
may affect replication = insertional mutagenesis: MAY BE
LATENT AND NEVER CAUSE NEOPLASIA
– HTLV-1 as above except insertion point varies –aberrant
viral protein may upregulate IL-2, IL-4, GM-CSF

12. Infections

13. Genetic/inherited factors
• Primary genetic diseases and leukaemia:
• Downs syndrome 20-30 fold increase in ALL or
AML,
• Bloom’s syndrome, Fanconi anaemia, ataxia-
telangiectasia,
• Weak familial link - B-CLL, HD, NHL - predisposing
genes not known
• Genetic alterations in utero – shown in studies on
ID twins : ALL with t(12;21)

14. Genetic abnormalities
• Whatever the cause - haematological
malignancies are associated with genetic
instability
• Normally cell proliferation and differentiation is
balanced by programmed cell death =
homeostasis
• Cancer = uncontrolled proliferation, lack of
differentiation and lack of apoptosis in clones of
malignantly transformed cells

15. NORMALITY vs ABNORMALITY at the
GENETIC LEVEL
• Within the normal human genome are highly conserved
genes called proto-oncogenes
– Proto = ancestral, from protos (protos) first
– Onco from onkos (onkos, denoting a tumour)
• Encode proteins - ie growth factors, growth factor
receptors, signal transducers, controllers of proliferation,
survival, differentiation and apoptosis
• Genetic alteration of proto-oncogenes may lead to
malignant transformation due to the generation of
abnormal proteins
• These abnormal genes = oncogenes ie. abnormal
counterparts of proto-oncogenes

17. Oncogenes

18. Tumour suppressor genes
• Mutations can occur in tumour suppressor genes
(anti-oncogenes) regulate proliferation – so
mutational inactivation may contribute to
tumourogenesis
• Activation of oncogenes and/or loss of tumour
suppressor gene function may result in
perturbation in proliferation, differentiation and
apoptosis AND it is likely that multiple genetic
changes are probably required within a cell for
malignant transformation
• MULTI-HIT THEORY

20. Genetic changes involved with malignant
transformation : translocations and inversions
• Translocations – most studied – frequent in leukaemias +
lymphomas :
– Sections of chromosome break - relocate elsewhere on the same
chromosome or to another – alters gene function or action of the
gene product.
• Ph chromosome in CML = reciprocal translocation of 2
normally separate genes : ABL from the long arm of chrom 9
and BCR from the long arm of chrom 22 = t(9;22).
• Two fusion genes result : BCR-ABL and ABL-BCR - latter plays
no role in the pathogenesis of the disease
• BCR-ABL fusion gene
– encodes for increased tyrosine kinase activity
– may inhibit apoptosis

24. Acute promyelocytic leukaemia (APL,
M3)
• Characterised by translocation of genes on
chromosomes 15 and 17, t(15;17).
• The resultant PML-RARα fusion protein
functions as a transcriptional repressor
whereas the normal RARα protein is an
activator.
• Result is a differentiation block

26. Acute promyelocytic leukaemia (APL, M3)
• Characterised by translocation of genes on
chromosomes 15 and 17, t(15;17).
• The resultant PML-RARα fusion protein
functions as a transcriptional repressor whereas
the normal RARα protein is an activator.
• Result is a differentiation block
• ATRA treatment selectively degrades the PML
RARα protein product so promoting normal
differentiation of cells and inducing remission.

27. Translocations involving the core binding
factor (CBF) genes
• CBF = heterodimeric transcription factor
important in regulating expression of many
genes ie IL-3 and GM-CSF
• The genes encoding the 2 components of CBF
(CBFα and CBFβ) are involved in a number of
chromosomal translocations in leukaemia e.g.
– t(8;21) in which CBFα gene (AML 1) is translocated
onto the ETO gene on chromosome 8

28. Inversions
• Inversions – AML inv(16)(p13.1q32) or t(16:16)
(p13.1q32), [M2 in FAB classification] results in
chimeric transcription factor which inhibits
normal maturation and development of
haematopoietic cells
– inv(3) (q21q26) are noted in a small proportion of
AML patients of M1, M2, M4, M6 and M7 sub-types.
• This inversion confers tri-lineage myelodysplasia
with notable abnormalities in the
megakaryocytic series

29. Deletion and Numeric Changes
• Deletion and Numeric Changes = loss or gain of part or
all of a chromosome.
– Chromosomal trisomy is associated with over expression of
genes.
– Deletions can result in cells resistant to normal growth control
mechanisms –often loss of a tumour suppressor gene
• Trisomy 8 is the most common numeric abnormality in
AML
• Trisomy 21 is associated with Downs
– predisposition to AML
• Partial /total loss of chromosomes 5,7 or Y and trisomy 8
= common in MDS

30. Point Mutations
Point Mutations in proto-oncogenes can cause
alteration in gene function
– ..AGCTCGG.. ..AGTTCGG
• Many human tumours have point mutations to
the ras family of genes, 20-30% in AML, 15-
20% in ALL, 20% in MDS
• The ras genes encode protein involved with the
transduction of receptor-mediated external
signals into the cell from the inner surface of
the plasma membrane

31. Point Mutations
• Oncogenic ras (due to single base
substitutions) may upregulate the proliferative
signal
– autonomous-autocrine proliferation.
• Approx. 20% of CML patients in transformation
have point mutations or deletions in the coding
sequence of the p53 tumour suppressor gene

32. Gene Amplification
Gene Amplification involves repeated replication
of short DNA segments – oncogene over-
expression seen in many tumours.
• Extra copies of the Ph+ chromosome in CML=
hallmark of disease progression from chronic to
acute phase.
• The gene encoding cyclin D1 is over-expressed
by gene amplification mantle cell lymphoma -
cells are driven into cell cycle beyond G1 in the
absence of normal growth factor stimulation

34. Mutations in tumour suppressor genes
contribute to neoplasms
• The anti-oncogene/tumour suppressor gene p53
normally encodes a 53KDa transcription factor
control protein.
• Expression of p53 is induced in response to DNA
damage
• p53 mediates cell cycle block at G1/S boundary to
enable the cell to repair DNA prior to entry to the
DNA replicative phase
• If DNA repair fails then p53 initiates apoptosis via
increased expression of the BAX gene

37. Mutations in tumour suppressor genes
contribute to neoplasms
• P53 mutations seen in many
leukaemias/lymphomas - underlies the
inherent genetic instability of cancer cells via
perpetuation of acquired genetic changes.

38. Oncogenes as anti-apoptosis genes
• Some cancer cells are resistant to apoptosis – due in part
to the aberrant expression of genes controlling apoptosis
• eg. translocation of BCL-2 gene from chrom 14 to 18
t(14:18) in 85% the follicular lymphomas, diffuse
lymphoma and B-CLL
• Results in constitutive bcl-2 expression - protects cells
from apoptosis.
• Accumulation of long lived neoplastic cells
• Mutant bcl-2 - associated with poor prognosis.
• May protect cancer cells from apoptotic effects of anti-
cancer therapy

40. Epigenetic alterations
• Something that affects a cell, organ or
individual without directly affecting its DNA.
An epigenetic change may indirectly influence
the expression of the genome
• DNA methylation or deacetylation of histones
suppresses gene transcription

42. THANK YOU