Neoplasia (rewatch Lc)
17 important questions on Neoplasia (rewatch Lc)
What is malignant lymphoma ?
- Lymfklierkanker
- Tumors of B/T cells in the lymph nodes and/or extranodal sites (some leukemic forms as well)
Antigen receptors and clonality analysis (lymphoma)
- Lymphoma is in principle clonal disease
- clonality detection as supplementary test
- for diagnostics of lymphoma
- highly diverse antibodies
- detection of monoclonal cells versus polyclonal cells based on the antigen receptor
- taking into account the diversity mechanisms:
- Gene shuffling (rearrangement)
- somatic hypermutation
Where can we find B-cell development and what characterises it?
- B cell development in the bone marrow
- heavy chain rearrangement
- light chain rearrangement
- B cell development in secondary lymphoid tissues
- differentiation into mature B lymphocytes
- maturation into plasma cells and memory cells
- various B cell tumors represent different stages in the B cell development
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Name some mechanisms of antibody diversity:
- Diversity of antigen receptors: > 10^12
- diversity via expression of different antigen receptors
- expression of antigen receptors is not individually regulated (in contrast to other genes: individual transcription, translation, splicing)
- gene shuffling: genomic rearrangments
What about maturation of B-cells in secondary lymphoid tissues?
- Immature B cells developed in the bone marrow between blood and secondary lymphoid tissue
- development from immature into mature B-cells occurs within secondary lymphoid tissue
- enter the lymph node through walls, guided by chemokine to primary lymphoid follies; this is the network of follicular dendritic cells
- contact follicular dendritic cells and B-cells:
- no encounter with antigen: B-cells detaches and goes back into the circulation; now developed into mature naive B cells
Molecular diagnostics lymphoma, the diagnosis is based on ?
immunohistochemistry (marker expression)
chromosomal aberrations
clonality detection
What do we mean with chromosomal translocations?
- Gene A will be chromosomal rearranged and becomes under the control of gene B (via promotor or enhance)
- tissue specificity
- extent and timing of gene expression
What is the preferred source of detection of this translocation? RNA or DNA?
because there is no fusion transcript, because the level of regulation is dependent on regulation, but the transcripts itself (so the exons that are coding) are the same for the BCL2 gene.
(and overall DNA is easier to work with)
What do you see in a fluorescence in situ hybridisation of a translocation?
How does molecular IG (of TR) clonality analysis work?
- PCR approach
- primers directed against J-genes
- Primers directed against V genes, using V-family specific primers, so primers VH3 anneals to V3.1, V3.2 etc
- Multiplex PCR
- separation of generated PCR products, using GeneScanning:
- exploits heterogeneity of the amplicon size of the PCR products
fluorescent labelled primer
capillaire electrophoresis
Somatic hypermutation of immunoglobulin genes
What does MYC enhance?
Because of what can a gene rearrangement go unnoticed?
High detection rate of clonal rearrangements
- analysis of the IGH in three frameworks
- analysis of light chain rearrangements
What is the function of JAK2?
mutated in MPN
Use of rearrangements as clonal markes
- Diversity of different IG/TR gene rearrangement
- gene rearrangement occur early in development of the B cell (pro/pre B cell stage)
- gene rearrangement are stably present
Name two kind of chromosomal translocations:
(also kind of summary)
- Gene fusions (chimaeric transcript/protein)
- Genes under control of another promotor/enhancer
You need two know which one in order to choose the correct detection method!
PCR -> Gene fusions translocation
FISH -> enhancer translocation
(vm?)
See lecture again for correct detection method.
9
MYC -> 2. Enhancer translocation, FISH
BL (Burkitt lymphoma) -> 2. Enhancer translocation, FISH
FL (follicle lymphoma) -> 1. Gene fusions, PCR
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