The etiology and genetics of

hematological malignancies

Abdulrahman E. Algarni, PhD

Learning objectives

• The primary distinctions between myeloid and lymphoid cancers.

• Describe some conditions that may occur in malignant haematology.

• The evolution of haematological malignancy

• The clinical diagnosis of haematological malignancy

• The laboratory diagnosis of haematological malignancy

 Introduction

• Haemato-oncology is the study of malignancies of the haemopoietic

system.
• The term 'haematological malignancy' refers to a variety of
malignant diseases affecting the haemopoietic system and serves to
distinguish them from malignancies of other tissues.
• Haemato-oncology is an enthralling field that allows scientists to
operate at the cellular, molecular, or genetic level, allowing doctors
to put together a diverse set of facts for an appropriate diagnosis.
Haematological malignancies
• Haematological malignancies are complicated and are classified differently by
different individuals and organizations.
• They are broken down into separate categories according to the current
perception of the cell of origin, the tissue in which they usually arise, the
molecular basis of the clonal proliferation and any specific characteristics.
• Can be classified as simply as possible:
üMyeloproliferative disorders: bone marrow disorders resulting in excess of one
or more types of myeloid cell (i.e. proliferation of blood cells)
üMyelodysplastic syndromes: a diverse group of bone marrow disorders that
result in the clonal production of abnormal (dysplastic) myeloid cells. These cells
fail to mature properly, resulting in blast (immature) cells
üLeukaemias is a collection of diseases that result in a clonal proliferation of white
blood cells
üLymphomas: clonal proliferations of lymphoid cells, mainly from lymph nodes
and extranodal tissue
üMyeloma: a malignant proliferation of plasma cells (Healthy plasma cells help
you fight infections by making antibodies that recognize and attack germs).
 Leukaemia and lymphoma

• Leukaemia is a term that refers to the presence of malignant

haemopoietic cells in the blood or bone marrow. These malignant cells
may be myeloid (red blood cells, neutrophils, monocytes, eosinophils,
basophils, or platelets) or lymphoid (B-lineage, T-lineage lymphocytes,
plasma cells, Natural Killer (NK) cells, or their precursors).
• Lymphomas are exclusively lymphoid in origin and are often limited to
lymphoid organs (spleen or lymph nodes. Frequently, lymphomas
progress into a leukemic phase, during which malignant lymphoid cells
that were previously confined to a specific lymphoid organ overspread
into the bone marrow and peripheral circulation.
The incidence and background of hematological neoplasms

• Cancer is an increasingly important cause of morbidity and mortality.

• Hematological malignancies represent approximately 8% of all malignant disease .

• There are major geographical variations in occurrence of the diseases; for example,
chronic lymphocytic leukemia (CLL) is the most common leukemia in the West but
rare in the Far East.

• There are four major subsets of leukaemia, but there is great heterogeneity within
each of these.

• Leukaemia, the term means white blood.

 The aetiology of haemopoietic malignancy

ØInherited factors
The incidence of leukemia is greatly increased in some genetic
diseases, particularly Down’ s syndrome where acute leukemia
occurs with a 20 - to 30-fold increased frequency. Additional
disorders such as Bloom’s syndrome, Fanconi’s anemia,
Klinefelter’ s syndrome.
ØEnvironmental influences

1. Chemicals:
Chronic exposure to benzene is an unusual cause of myelodysplasia or
AML. Other industrial solvents and chemicals less
commonly cause leukemia.
2. Drugs:
The alkylating agents (e.g., chlorambucil, procarbazine and
nitrosoureas predispose to AML, especially if combined with
radiotherapy, Immunosuppressive drugs
3. Radiation
Radiation, especially to the marrow, is leukaemogenic. This increased incidence of all
types of leukemia e.g.: in the atom bomb explosions in Japan.

4. Infection
vViral infection is associated with several types of hemopoietic
malignancy:
üHuman T- lymphotropic virus type 1 is the cause of adult T - cell leukemia
/lymphoma.
üEpstein - Barr virus (EBV) is associated with Burkitt lymphoma.
üHuman herpes virus is associated with Kaposi’s sarcoma and lymphoma.
üHIV-1 infection is associated with an increased incidence of High-grade
B-cell lymphomas .
vBacterial infection:

Helicobacter pylori infection has been implicated in the pathogenesis

of gastric mucosa B - cell lymphoma.

vProtozoa:

Malaria = Burkitt's lymphoma.

Endemic Burkitt lymphoma occurs in the tropics, particularly in

malarial areas
 The genetics of haemopoietic malignancy

• Malignant transformation occurs as a result of the

accumulation of genetic mutations in cellular genes.

• The genes that are involved in the development of cancer

can be divided broadly into two groups: oncogenes and

tumour - suppressor genes .

 Oncogenes
qOncogenes arise due to function mutations in normal
cellular genes called proto-oncogenes.
qProto-oncogenes act as central regulators of growth in
normal cells, when altered or mutated, they become
oncogenes
qOncogenic versions are generated when the activity of
proto-oncogenes is increased, or they acquire a novel
function. This can occur in a number of ways including
translocation, mutation or duplication.
Proliferation of normal cells depends on a balance between the action of proto -
oncogenes and tumor-suppressor genes. In a malignant cell this balance is
disturbed leading to uncontrolled cell division.
 Tumour-suppressor genes

§ Tumour suppressor genes usually present in our cells they control

the cell growth and programmed cell death (apoptosis). When
mutated this will lead to tumour formation or growth.

§ Mutations of tumor suppressor genes are acquired because of

environmental factors (carcinogens)

§ Tumour - suppressor genes may acquire loss - of - function usually by

point mutation or deletion, which lead to malignant transformation.
 Tumour protein 53 (P 53)

• Also known as TP53.

• Known as the genome guard because it preventing genome

mutations.

• p53 which is mutated or inactivated in over 50% of cases of

malignant disease.

• Activate DNA repair proteins when DNA is damaged.

• Play role in apoptosis

• Are a group of disorders characterized by the accumulation of
malignant white cells in the bone marrow before disseminating to
the peripheral blood, lymph nodes, and other organ.
• The exact cause of leukemia is unknown. Both inherited and
environmental (non-inherited) factors are believed to be involved.
• Risk factors include smoking, ionizing radiation, some chemicals
(such as benzene), prior chemotherapy, and Down syndrome. People
with a family history of leukemia are also at higher risk.
These abnormal cells cause symptoms because of:

(i) Bone marrow failure:

(e.g., anemia, neutropenia, thrombocytopenia).

(ii) Infiltration of organs:

(e.g., liver, spleen, lymph nodes, meninges, brain, skin or testes).

Clinical feature results from the following:

A- Bone marrow failure:

1. Anemia :(pallor ,easy fatigability and dyspnea).
2. Neutropenia: (fever, respiratory infection, recurrent mouth and
skin infection.
3. Thrombocytopenia:(Spontaneous bruises, purpura, bleeding
gums and menorrhagia) and bleeding due to disseminated
intravascular coagulation (DIC) in AML-M3 .
B. Organ infiltration:

1. Lymph node enlargement: more common in ALL.

2. Hepatosplenomegaly.
3. Skin infiltration.
4. Gum hypertrophy and infiltration of skin and CNS.
Clinical findings cont.….
Acute Chronic

Age All ages Adults

Clinical onset Sudden Insidious

Course (untreated) <6/12 2-6 years

Blast count in the marrow >20% blasts (WHO) More mature

Anaemia Prominent Mild

Thrombocytopenia/ thrombocytosis Prominent Mild

WBC count Variable Increased

Lymphadenopathy Mild Often present

Hepatosplenomegaly Mild Often present

Leukemia classified by the type of white blood cell affected
(Lymphoid or Myeloid) and by the clinical course of the disease
(Acute or Chronic).

ü Acute leukaemias are usually aggressive diseases in which

malignant transformation occurs in the haemopoietic stem cell or
early progenitors. Genetic damage is believed to involve several
key biochemical steps resulting in:
• Increased rate of proliferation.
• Reduced apoptosis and .
• Block in cellular differentiation.
 Acute VS Chronic Leukemia
• The clinical symptoms, maturity of the affected cells, and total leukocyte count determine
whether a leukemia is classified as acute or chronic.
• Acute leukemias are characterized by symptoms of short duration, many immature cell
forms in the bone marrow and/or peripheral blood, and an elevated total leukocyte count.
• Chronic leukemia have symptoms of long duration, mostly mature cell forms in the bone
marrow and/or peripheral blood, and total leukocyte counts extremely elevated.
• The prognosis of survival in untreated acute forms is from several weeks to several months,
compared with the untreated chronic forms, which can have a prognosis of survival ranging
from months to many years after diagnosis.
• Acute leukaemia is associated with an accumulation of immature cells called blast—
comprising at least 20% of the nucleated cells of the bone marrow with evidence of
maturational arrest.
• Acute leukaemias are also clinically aggressive, leading to death relatively rapidly if
untreated.
• Chronic leukaemias are less aggressive and have blasts below 20%.
 EPIDEMIOLOGY OF ACUTE LEUKEMIAS
• According to the National Cancer Institute, there were an estimated
44,790 new cases of leukaemia and an estimated 21,870 deaths
from leukaemia in the United States in 2009.
• AML remains a lethal disorder, which kills the majority of affected
adults. Nearly 70% of adult patients with acute leukaemia
ultimately die of infection. The median survival time for an
untreated patient with acute leukaemia is 3 months
• More than 25% of adults with AML can be expected to survive three
or more years and may be cured.
Diagnostic methods used to study malignant cells

• Morphology

ü Blast cells

ü NRBC’s

ü Useful in an emergency
• Karyotype analysis
Karyotype analysis involves direct morphological analysis of chromosomes from tumour cells
under the microscope.
• Fluorescence in situ hybridization analysis
Fluorescence in situ hybridization (FISH) analysis involves the use of fluorescent-labelled
genetic probes which hybridize to specific parts of the genome.
• Gene sequencing
Gene sequence analysis is used to detect the genetic mutations that can cause malignant
disease. Next generation sequencing (NGS) can be used to study individual genes of interest;
sequencing of the whole exome or genome of the cancer
• DNA microarray platforms
DNA microarrays allow a rapid and comprehensive analysis of the pattern of cellular
transcription within a cell or tissue by hybridizing labelled cellular mRNA to DNA probes
which are immobilized on a slide or microchip.
• Flow cytometry
In this technique, antibodies labelled with different fluorochromes recognize the pattern and
intensity of expression of different antigens on the surface of normal and leukaemic cells
• Immunohistology (immunocytochemistry)
Antibodies can also be used to stain tissue sections
 Morphology Cytogenetics Immunophenotyping

Cytochemistry FISH MOLECULAR