Introduction To Haematological Malignancies

Introduction to Haematological Malignancies
 The genes involved in development of cancer can be broadly divided into 2:

i. Oncogenes
ii. Tumour-suppressor genes
Oncogenes
 Oncogenes arise because of gain-of-function mutations in normal cellular genes
called proto-oncogenes
- Proto-oncogenes are involved in the pathway by which external signals are
transduced to the cell nucleus to activate genes.
- Oncogenic versions are generated when the activity of proto-oncogenes is
increased, or they acquire novel function
o This can occur through translocation, mutation or duplication
o Haematological malignancies have high frequencies of chromosomal
translocation
- Consequences of Translocation:
i. Overexpression
o e.g. in Lymphoid malignancies
ii. Fusion of segments of two genes creating a novel fusion gene and hence
fusion protein
o E.g. in Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia
- A sub-set of proto-oncogenes are involved in control of apoptosis

o E.g. BCL-2 is overexpressed in follicular lymphoma.
Tumour-suppressor genes
 Tumour –suppressor genes may acquire loss-of-function mutations, usually by point

mutation or deletion, which leads to malignant transformation
 TSGs regulates entry of the cell from the G1 phase of the cell cycle into the S phase
or passage through the S phase to G2 and mitosis
Telomere
 Telomeres are repetitive sequences at the ends of chromosomes.
 They decrease by 200 base pairs of DNAs with every round of replication
o When they decrease to a critical length, the cell exists from cell cycle
 Germ cells and stem cells that need to self-renew and maintain a high proliferation
potential contain an enzyme telomerase that can add extensions to the telomeric
repeats and compensate for loss at replication and so enable the cells to continue
proliferation
 Telomerase is also often expressed in malignant cells, but this is probably a
consequence of the malignant transformation rather than initiating factor
Janus kinases (JAKs)
 JAKs are receptor-associated tyrosine kinases involved in intracellular signalling

pathways of cytokines and growth factor receptors
 JAK 2 transduces signals from multiple growth factor receptors.
 Activation of JAKs occurs as a result of ligand-induced aggregation of receptor
associated JAKs
 Other genes
o Breakpoint Cluster Region (BCR)gene
o Abelson (ABL)
o Calreticulin (CALR) gene
Classification of leukaemia
 Acute lymphoid/lymphoblastic leukaemia (ALL)

 Chronic lymphoid/lymphoblastic leukaemia (CLL)
 Acute myeloid leukaemia (AML)
 Chronic myeloid leukaemia (CML)
Acute Leukaemia’s
Risk factors
 Acquired
- Cytotoxic chemotherapy
- Haematological e.g. myelodysplasia (AML)
 Inherited
- DNA repair defects, immune defects
- Other e.g. Down syndrome
Investigations
 History and examination
 Bloods
- FBC (anaemia, thrombocytopenia, hyperleukocytosis, neutropenia)
- Smear (blasts, dysplastic neutrophils (2º AML))
- U&Es (hyperuricaemia)
- LDH
- Clotting screen
- LFTs, BUN/creatinine ratio
- Septic screen (if infection suspected)
 Imaging
- CXR, CT (pneumonia, mediastinal mass, lytic bone lesions)
 Bone Marrow biopsy
- Flow cytometry, cytogenetics and immunohistochemistry
- >30% blasts
Acute Lymphoblastic Anaemia
 Also known as ‘lymphocytic’

 Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the
bone marrow
Epidemiology
 M>
 Commonest type of childhood leukaemia (70%)
 Peak age 2-5 years, but later increase >50
Pathophysiology
 Formation of fusion genes leads to dysregulation of proto-oncogene
o e.g. TEL-AML1 (25%)
 85% are derived from B-Cell precursors
Findings specific to ALL
 Examination
- Lymphadenopathy
- Splenomegaly (10-20% presentation)
- CNS signs- more likely
 Bloods
- Anaemia- usually severe, signs present
- WBCs- variable, usually neutropenia
- Smear- smallish basophilic blasts, few granules, hand-mirror cells
- Clotting- 10% ALL presents with DIC
 Imaging
- Mediastinal mass in some T cell ALL
Acute Myeloid Leukaemia
 Aka ‘myelogenous’
Epidemiology
 M>
 Commonest type of adult leukaemia (90%)
 Can occur at any age but median is 70 years
Pathophysiology
Two classes of mutations may be required, like

ALL:
Findings
 Examination
- Lymphadenopathy unusual
- Leukaemia cutis (10%), chloroma (rare)
 Bloods
- Anaemia- usually severe, signs present
- WBCs- variable, usually neutropenia
- Smear- Auer rods in large hypergranular myeloblasts
- Hypokalaemia in monocytic leukaemia
- Clotting- DIC commoner in acute promyelocytic leukaemia (M3)

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Introduction to Haematological Malignancies

 The genes involved in development of cancer can be broadly divided into 2:

- A sub-set of proto-oncogenes are involved in control of apoptosis

 Tumour –suppressor genes may acquire loss-of-function mutations, usually by point

 JAKs are receptor-associated tyrosine kinases involved in intracellular signalling

 Acute lymphoid/lymphoblastic leukaemia (ALL)

 Also known as ‘lymphocytic’

Findings specific to ALL

Acute Myeloid Leukaemia

Two classes of mutations may be required, like

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