Introduction To Leukaemia And Malignant Haematology Flashcards
Aetiology of haematological malignancy?
Speak a little about each.
Combination of genetic and environmental factors.
Genetic Eg) Downs Syndrome
What is a haemopoietic malaignancy?
A clonal disease that is derived from a single cell in the bone marrow or lymphoid tissue which has undergone genetic alteration.
Environmental factors involved in haematological malignancy?
Chemicals eg) benzene –> AML
Drugs, especially previus chemotherapy –> AML
Radiation eg) atom bomb survivors in Japan
Infections
Can you name some infectious agents associated with haematological milignancies?
Viral: EBV and Burkitts lymphoma HHV8 and Kaposi's Sarcoma Bacterial: H. Pylori and gastric MALT lymphoma
What are haematological growth factors?
Soluble glycoprotein hormones.
Site of action of haematological growth factors?
May act locally at a site where produced or circulate in plasma.
What kinds of cells produce haemopoietic growth factors?
Many kinds of cells Eg) T lymphocytes, endothelial cells
Mainly stromal cells of the bone marrow Eg) adipocytes, fibroblasts, endothelial cells, macrophages/monocytes
What are stromal cells and what do they do?
Connective tissue cells of any organ. They support the function of the parenchymal cells of that organ.
What do haemopoietic growth factors do?
They interact at many different levels in the bone marrow, from stem cell to mature blood cell, to regulate proliferation and differentiation of haemopoietic progenitors.
How do haemopoietic growth factors exert their effect?
Exert their effect by binding to high affinity receptors on the cell surface.
Which haemopoietic growth factor stimulates erythropoiesis?
Where is it produced?
Erythropoietin.
Mainly in kidney but also in liver(early development)
Which haemopoietic growth factor is involved in platelet production? Where is it produced?
What does it do?
Thrombopoietin.
Produced by liver and kidney.
Stimulates the production of megakaryocytes.
What are megakaryocytes?
Bone marrow cells that bud off large numbers of platelets.
What is a cytokine? Examples?
Cytokines are a broad and loose category of small proteins that are important in cell signalling.
Cytokines include chemokines, interferons, interleukins, lymphokines and tumour necrosis factor.
What are interleukins?
What do they do?
Interleukins are a group of cytokines that were first seen to be expressed by WBC’s (leukocytes).
They promote the development and differentiation of T and B lymphocytes, and haematopoietic cells. (Includes NK cell)
For what is stem cell factor important?
Plays an important role in haematopoiesis, spermatogenesis and melanogenesis.
What are granulocytes/polymorphonuclear leukocytes (PMN)?
A category of WBC’s characterised by the presence of granules in their cytoplasm.
Types: neutrophils, basophils, eosinophils and mast cells
Growth factors associated with: -RBC's -Platelets -Monocytes -Neutrophils -Eosinophils -
RBC's - erythropoietin Platelets - thrombopoietin Monocytes - M-CSF Neutrophils - G-CSF Eosinophils - IL-5
What aspects of cell development do haematopoietic growth factors promote?
Proliferation Differentiation Maturation Suppression of apoptosis Functional activation
Mechanism of action of haemopoietic growth factors?
1) GF binds to corresponding receptor (dimerisation)
2) binding activates whatever pathway is involved
3) activation of pathway –> transcription of particular genes
Ist three secondary pathways that may be activated by a haemopoietic growth factor.
JAK/STAT pathway
MPK pathway
Phosphatidyl-inositol-3-kinase (PI3K) pathway
Which transcription factor is needed for cell transition from G1 to S phase?
E2F
Which gene codes for a protein that inhibits the action of E2F?
How is this gene activated?
Rb (retinoblastoma) gene.
Gene is activated by p53.
What is AKT?
A protein kinase that suppresses apoptosis.
Outline the cell cycle.
M phase - mitosis, cell physically divides
Interphase:
-Where chromosomes duplicate and cell growth occurs prior to division
What are the 3 stages of interphase?
G1 - cell begins to commit to replication
S phase - DNA content doubles and chromosomes replicate
G2 - cell organelles copied and cytoplasmic volume increases
What are the roles of checkpoints in the cell cycle?
When do they occur?
Checkpoints act as breaks to coordinate divisions.
These breaks allow integrity of DNA to be assessed - does DNA need to be repaired?
They occur either side of S-phase.
Which group of enzymes is responsible for progression through the cell cycle?
Cyclin-dependent protein kinases (Cdk’s)
Which two classes of molecules control the checkpoints in the cell-cycle?
Cyclins
Cyclin-dependent kinases (Cdk’s)
How is p53 involved in the cell cycle?
Acts at the G1-S checkpoint to sense damaged DNA.
p53 prevents activation of Cyclins required for the movement through the checkpoint –> allows time for repair of a potential defect.
When the defect cannot be repaired the cell undergoes apoptosis.
Outlone the processof apoptosis.
1) Activation of caspases
2) Cell shrinkage
3) Cleavage of DNA
4) Condensation of nuclear chromatin
5) Fragmentation of nucleus
6) Phagocytosis of apoptotic bodies by macrophages
2 main stimuli for the initiation of apoptosis?
Cell receptors: FAS/FASL
Release of cytocrome c from the mitochondria
An example of a cell that expresses FASL?
Cytotoxic T-cells
What do BAX proteins do?
Which protein upregulates expression of BAX?
BAX increases permeability of mitochondrial membrane –> cytochrome C release (tends to apoptosis).
p53 up-regulates BAX
What is Bcl-2 and what does it do?
What group of genes does it fall under?
Bcl-2 is an antiapoptotic protein that makes mitochondrial membrane less permeable –> less cytochrome C (tends away from apoptosis).
BCL-2 is a proto-oncogene.
2 main genes involved in the development of cancer?
Oncogenes
Tumour surpressor genes
Can a translocation on a chromosome be visible under a microscope?
Yes.
Which genetic alteration is associated with Chronic Myeloid Leukaemia?
t(9;22)
Which genetic alteration is associated with Acute Promyelocytic Leukaemia?
t(15;17)
Which genetic alteration is associated with Burkitt lymphoma?
t(8;14)
What is the role of a tumour surpressor gene and give an example.
It is a gene responsible for protecting the organism against malignancy and regulating the cell cycle.
p53 is the most significant tumour surpressor gene.
List the five main genetic abnormalities underlying haematopoietic malignancies.
Point mutation Translocation Partial chromosomal deletion Chromosomal duplication DNA methylation/deacetylation (epigenetic alterations)
Two mechanisms by which a translocation may caise haematological malignancy?
1) via the creation of a fusion gene, where 2 separate codings for different proteins end up together to produce a combination protein.
2) dysregulation, where an enhancer region (or any region that regulates rate of transcription) of one region is placed before a DNA sequence that it is not usually next to, cuasing increased or decreased transcription.
Characteristivs of the cells in acute leukaemia?
Acute implies that the proliferating cells are at an early stage of development (not very differentiated).
Characteristics of the cells in chronic leukaemia?
Cells are able to mature (are differentiated).
They often lose normal function and accumulate due to failure of apoptosis mechanisms.
Outline the progression of acute leukaemia.
Characteristic of the cells involved?
Chemotherapy?
Onset is rapid –> death within weeks or months.
Cells involved have a defect that stops them from maturing or dying.
Requires high dose chemotherapy.
Outline the progression of chronic leukaemia.
Characteristic of the cells involved?
Therapy?
Types?
Onset is slow –> death in months to years.
Proliferating cells retain their ability to differentiate.
May not require treatment. May require oral therapy or less intensive chemotherapy as opposed to that of acute.
2 types: myeloid/lymphoid
What does the term myeloid mean?
Is an adjective that relates to the granulocyte precursor cell in the bone marrow.
What does lymphoid mean?
In relation to leukaemia?
Resembling or pertaining to lymph or tissue of the lymphoid tissue.
When referring to leukaemia, it is a type of leukaemia affecting circulating lymphocyte cells.
What does WHO use in the classification of leukaemias?
Morphology
Identification of cell surface markers (flow cytometry)
Cytogenetics/karyotyping
Molecular genetics (FISH, PCR)
Is bone marrow failure common to all leukaemias or only some? Why does this occur?
Common to all leukaemias.
Occurs due to infiltration and disruption of normal tissue function.
What are the clinical effects of bone marrow failure?
Why do all leukaemias lead to bone marrow failure?
Bleeding (low platelet count)
Infections (immune deficiency - such as neutropenia)
Anaemia (decreased RBC production) –> fatigue + pallor
Occurs due to malignant cells infiltrating and disrupting normal bone marrow tissue.
Which organs can be involved in ALL?
Bone pain. (Commoner in children)
Testicular pain.
What is seen commonly in AML?
Gum hypertrophy.
In which group of leukaemias is lymphodenopathy and hepatosplenomegaly seen in?
Mostly chronic leukaemias. Some ALL.
What metabolic abnormalities are associated with ALL and Burkitt’s Lymphoma.
Tumour lysis - acute rise in uric acid, K and phosphate.
Hyperuricaemia.
Fever.
