Leukaemia Flashcards
- Proto-oncogene
- Tumour suppressor gene
- Oncogene
- Proto-oncogenes code for proteins that normally involves in pathways stimulating cell division, proliferation and differentiation. Mutation of or over activity and gain of function results in ONCOGENES causing over-proliferation and over-promotes cell division
- Normal regulators of cell proliferation. Mutation or deletion results in over-proliferation and ‘loss of function’ so that negative reg function is lost, allowing proliferation to carry on unopposed
- Malignant change in structure of Proto- oncogene which now encodes for abnormal proteins that can induce and maintain malignant transformation and proliferation of the clone
Two main mechanisms of Apoptosis
- Receptor mediated pathway: via a death receptor binding a death receptor FAS/TNFligand on cell surface. Activates the caspase which are the executors
- Via mitochondria. They detect irreparable DNA (cellular constituents) and trigger release of cytochrome c (bcl family) controls and increases permeability of mitochondrial membrane. Cytochrome c interacts with apoptosis cascade to activate caspases –> APOPTOSIS
What is translocation? How and what does it result in?
Exchange of material between chromosomes resulting from an alteration of Proto-oncogenes resulting in one of two:
- Product of fusion genes- a part of one gene becomes attached to another. Interferes with structure, function and susceptibility to regulatory proteins
- Transfer of the gene to a site that is actively transcribed. Thus trams located gene falls under the influence of these stimulators mech. Eg. B lymphocyte malignancies, translocation occurs, oncogene moved to site of one of the immunoglobulin loci, then actively transcribed.
Characteristic feature of stem cells
Self-renewal and differentiation
Therefore able to produce daughter cells which have characteristic of stem cell or more differentiated cell.
Guided by presence of growth factors.
Why does it make sense that stem cells are cells of origin for malignancy?
Stem cell –> long lived, present for entire life span. There long enough to accumulate multiple genetic alterations necessary for malignant transformation. More differentiated cells have fewer rounds of cell division before maturing to end-stage
Stem cell –> feed the malignancy with new cells. More mature cells will feed with a few round of cell division
Stem cells –> have active transcription of regulatory genes, whereas in differentiated cell, many of these genes are switched off.
Phenotype of malignancy depends on:
- Cell lineage - myeloid vs lymphoid
- Proliferative rate - acute: high, chronic: low
- Degree of differentiation- acute: undifferentiated (blasts), chronic: differentiated to mature
- Amount of apoptosis
Various Chemotherapy drugs and their mechanisms
Topoisomerase : induces DNA strand breaks and inhibits mitosis
Antimetabolites: metabolite binds DNA and inhibits DNA polymerase.
Anthracyclin: bind DNA and interfere with mitosis
Explain the process of malignancy as a result of Gain of function
- amplification of gene: several copies of the gene occur
- mutation of gene: esp at the site important for regulation of function. The product is no longer sensitive to normal control mechanisms
- mutation of reg gene: Proto-oncogene becomes oncogene which functions unopposed
Translocation: an exchange of material between chromosomes
What are the two possible outcomes of translocation
A) production of a fusion gene- a part of one gene becomes attached to another gene. This interferes with the structure and consequently the function and susceptibility to regulatory proteins.
B) transfer of the gene to a site that is actively transcribed. In many b lymphocyte malignancy, translocations occur which move oncogenes to a site of one of the immunoglobulin loci, which is actively transcribed, and thus the translocated gene falls under the influence of these stimulatory mechanisms.
Explain loss of function in relation to malignant development
Loss of function:
- large deletions resulting in deletion of the gene
- small deletion, 1 or 2 bases, which result in reading frame-shifts of the sequence producing a totally different protein
- mutations resulting in STOP codons.
- mutations in the promoter sequence of gene so there is a decreased expression
- mutations in the splice region of the gene- aberrant splicing at the mRNA level also reduces synthesis of the active protein.
Caspase action:
Cytoskeleton change
Nuclear change
Cytoplasmic condensation
Nuclear fragmentation
Apoptosis vs Necrosis
Apoptosis: physiological condition by which cells are committed to suicide through an orderly regulated cell death (programmed) by cytokines.
Necrosis: non-physiological process resulting after acute injury.
Apoptosis:
Lose intercellular adhesion
Fragment the chromatin
Break into apoptotic body engulfed by macrophages.
Necrosis:
Release of cytoplasmic and nuclear cell content into environment.
AML treatment
• antimetabolite- it’s metabolite is incorporated in DNA and inhibits DNA polymerase.
S/E: bone marrow suppression, liver and CNS side effects
•anthracyclins- binds to DNA and interferes with mitosis!
S/E: BM suppression, cardiotoxicity
•topoisomerase inhibitor: induces DNA strand breaks and inhibits mitosis
S/E: BM suppression
