MISC Flashcards
Describe the normal cell cycle using a detailed
annotated diagram [2 for diagram + 4 for annotations]
At both checkpoints, if DNA is not satisfactory for the
next phase, DNA repair takes place OR apoptosis occurs
Name the most important protein involved with cell
cycle regulation at the G1/S checkpoint (½)
p53
Outline three (3) molecular mechanisms whereby haematologic malignancies may develop (3) (Super NB)
- Gain of function of proto-oncogenes
- Mutations in tumour suppressor genes
- Defects in apoptotic pathway, so cells do not die but accumulate
List four (4) genetic mechanisms which may underlie haematologic malignancies (4 x ½ = 2)
Point mutations,
Translocations, Chromosomal deletions, Chromosomal duplications,
DNA methylation/ histone deacetylation
Outline three attributes/characteristics of tumour suppressor genes (3)
Responsible for protecting the organism against malignancy & regulating
the cell cycle. Loss of normal tumour suppressor gene function occurs due to loss of function mutations (point mutation/ deletion) and this may lead development of malignancy. TP53 is the most significant tumour suppressor gene in human cancer and is mutated or inactivated in >50% of malignancies.
Define proto-oncogenes and outline their functions (3) (Super NB)
Normal genes that code for proteins which are involved in the regulation of cell growth, proliferation and differentiation.
Outline how a proto-oncogene may be involved in leukaemogenesis (2) (NB)
Malignancy arises as a result of change of structure/gain-of function of a proto-oncogene into an oncogene leading to uncontrolled proliferation.
Leukaemia may arise as a result of alterations in oncogenes. Outline three (3) molecular mechanisms whereby loss of function of oncogenes may occur (4½) (NB)
Large deletions with deletion of oncogene
Small deletions of only a few bases, causing frame shift and production of a different protein.
Mutations that result in STOP codons so protein not produced
Mutations in promoter sequence of gene that cause decreased gene expression.
Mutations in splice regions of gene, with aberrant mRNA splicing decreased synthesis of protein.
The high proliferation rate of cells in acute leukaemia is thought to be the result of the unregulated activity of oncogenes. Describe the mechanisms that may result in gain of function of oncogenes (4) (Super NB)
“Gain of function” of an oncogene may result from:
Amplification of the gene so that several copies of the gene occur.
Mutation of the gene – especially at sites which are important for regulation of gene function so that mutated gene is no longer responsive to normal control mechanisms.
Mutation of the regulators of the oncogene
Translocations with exchange of material between chromosomes which results in two situations
o Production of a fusion gene – part of oncogene is attached to another gene. This interferes with its function and susceptibility to regulatory control mechanisms.
o Transfer of the oncogene to a site which is actively transcribed. E.g. In many B lymphoid malignancies, translocations occur which move oncogenes to sites of immunoglobulin gene loci, which are actively transcribed, and so the translocated gene falls under the influence of these mechanisms.
Define apoptosis (1)
The regulated process (½) of physiological cell death (½)
Name and briefly describe two (2) cellular pathways leading to apoptosis (2x2 = 4)
Any two of:
Receptor-mediated pathway (½): Binding to the FAS/TNF receptor (½) on a target cell triggers the intracellular release of caspases (½) via activation of an intracellular death domain (½).
Mitochondrial pathway (½): Damage to the cell triggers release of cytochrome C (½) from mitochondria which activates caspases (½). BCL proteins (½) regulate the mitochondrial membranes
p53 pathway (½): p53 activates apoptosis by raising the level of BAX (½) which increases cytochrome C release (½) and shuts down the cell cycle to stop division (½)
Leukaemia may be associated with decreased rates of apoptosis. Outline the two (2) main mechanisms of activation of apoptosis in normal cells (3+3 = 6) (NB)
Receptor mediated pathway: A “death receptor” (e.g. tumour necrosis factor receptor) on the cell surface binds to its ligand and this triggers the activation of caspases which cause DNA digestion and disintegration of the cell skeleton.
If irreparable damage to cellular constituents (e.g. DNA) is detected, the mitochondria are triggered to release cytochrome c which causes activation of caspases and hence apoptosis.
List four (4) cellular events that occur after the activation of apoptosis by the pathways discussed above (½x4 = 2)
Cellular shrinkage, Cleavage of DNA, Condensation of nuclear chromatin, Condensation of cytoplasm, Nuclear fragmentation, Phagocytosis of apoptotic bodies by macrophages
Give an example of how a genetic event leads to the dysregulation of apoptosis and a haematological malignancy (4x½ = 2)
Any four including: t(14;18) translocation (½) in Follicular lymphoma (½) leads to the over expression of BCL2 (½). This reduces apoptosis (½) and causes the accumulation (½) of malignant cells.
Outline two (2) properties/ characteristic features of stem cells (2) (NB)
Self-renewal: Ability divide and replicate themselves to produce more stem cells
Multi-potentiality/ Differentiation: Ability to proliferate and undergo differentiation to more specialized cell types
Describe the properties of stem cells (3) (Super NB)
Stem cells have the capacity for self-renewal, as well as of differentiation. On division, the stem cell is therefore capable of producing “daughter cells” which have either the characteristics of a stem cell (the parent cell) or of a more differentiated cell.
Currently, we think that haematological malignancies originate from haemopoietic stem cells. Explain why a stem cell is a more likely target as the origin of haematological malignancies than a more differentiated cell (3)
Conceptually it makes sense that the stem cell is the cell of origin in a malignancy.
Remember that stem cells are extremely long lived as they are present for the entire lifespan of the individual. They are therefore around long enough to accumulate multiple genetic alterations. More differentiated cells have the capacity for only a few rounds of cell division before they die out, and therefore it is less likely that they live long enough to accumulate the range of genetic alterations for malignant transformation.
Stem cells have the capacity for self-renewal which means that they will constantly “feed” the malignancy with new cells. More differentiated cells will only be able to feed into the malignancy for a few rounds of cell division before dying out.
Stem cells have active transcription of the relevant regulatory proteins, whereas in the differentiated cells, many of these genes have been “switched off” during the process of differentiation. It is easier to “Hijack” an existing system, than to reactivate one which has been switched off.
Outline the cellular pathways by which apoptosis can occur (3)
Apoptosis may occur via antigen binding to cell receptors (1) e.g. FAS/TNF receptor OR release of cytochrome C (1) from mitochondria (1) leading to increased caspase (1) activity
Define haemopoeitic growth factors (2)
Soluble glycoprotein hormones (½) which regulate proliferation (1) and differentiation (1) of haemopoietic progenitor cells (1)
Describe how growth factors act on a cellular level (3)
The growth factor binds to the corresponding cell surface receptor (1) which dimerises (1). Binding activates various intracellular pathways including the JAK/STAT (1) and MAP kinase pathways (1) which increased transcription of particular genes (1
List any four (4) factors that would influence your treatment plan in a patient with CLL (2)
Patient factors: Age (½), performance status (½), co-morbidities (½)
Disease factors: Stage (½), symptoms (½), disease activity (½), prognostic factors (½)
Explain the predisposition to infection in a patient with CLL (3)
Immunosuppression due to hypogammmaglobulinaemia (1) and neutropenia (1) +/- defective cellular immunity (1)
Outline four (4) important laboratory tests (and their findings) used in the diagnosis and initial assessment of patients with plasma cell myeloma (4)
Serum protein electrophoresis (½): M-protein (½)
Urine light chain (½): >1g/24hr (½)
Serum free light chain (SFLC) assay (½): Elevated or abnormal SFLC ratio (½)
Bone marrow biopsy (½): BM clonal plasma cells (½)
Full blood count (FBC) (½): Anaemia ± neutropenia/thrombocytopenia (½)
Renal function tests (½): ± Renal impairment (½)
Calcium level (½): ± Elevated (½)
