week 19 p2 Flashcards
What is hematologic malignancy
Involves abnormal productions of blood cells and immune cells eg leukaemia and lymphoma
Why is genetic defects in HM important
· Many subtypes of acute and chronic leukaemia’s are linked with DNA changes
· Genetic lesions can be used as diagnosis ad prognosis
Also may lead to improvement in threptic approach using molecular defects
How is the overall survival in Acute myeloid leukaemia measured
· Detection of chromosomal abnormalities by cytogenetic analysis is important in diagnosis
What is the detection of AML in chromosome
Detection of (8;21) (5;17) (q22;q22,1)
What are the types of genetic lesions in HM
· Translocations that result in abnormal gene expression
· due to placement of genes near enhancer or promoter element of other genes
· Translocations that produce chimeric fusions proteins (proteins that create joining of two or more genes that originally for same or separate proteins) with biological activity
Mutations is known oncogenes/tumour suppressor genes
What is the consequences of translocation
· The immunoglobin gene (B cells is in the immunoglobin in the cell surface)
· Causes abnormal or altered expression of the normal protein produced by other gene
It is the abnormal expression, timing an levels are inked with malignant phenotype
How does the chromosomal translocation link to neoplasm(abnormal growth in cells)
give eg
· Follicular lymphoma, t(14;18), IgH-bcl-2 causes inhibition of apoptosis cyclin ( so cells do not die)
· Burkitt’s lymphoma, t(8;14), IgH,myc cause transcription factors
CML, t(9;22), bcr-abl causes tyrosine kinase
What is Philadelphia (ph) chromosomes
· Ph chromosomes is a cytogenetic defect that is seen as a shorten version of human chromosomes of 22 in CML
· Presented in 90-100% CML
And 25% of ALL
What is c-myc
· Is the prototype for oncogene activation by chromosomal translocation
· Regulated expression of c-myc in normal cells
c-myc is deregulated in human cancer
What is a Burkitt’s lymphoma
c-myc breakpoint differs in sporadic and endemic Burkitt’s
Varies the types as patients who have EBV are 97% likely to have endemic Burkitt’s
20-30% of are sporadic cases
What is a Burkitt’s lymphoma
c-myc breakpoint differs in sporadic and endemic Burkitt’s
Varies the types as patients who have EBV are 97% likely to have endemic Burkitt’s
20-30% of are sporadic cases
Describe the different types of Burkitt’s lymphoma
(8: 14- IgH
8: 22-IGbeta
2: 8- IGk
What defect does Ph have
T(9:22)(q32:q11)
C-abl in chromosome s9 (tyrosine kinase)
Bcr on chromosomes 22 (protein)
What lymphoma is it found
90-100% of adult CML
20-30% of adults ALL
5% in childhood ALL
What is shown in microscopy if you see chromosomes
Bacteria and chromosomes
Not viruses
What is BCR-ABL protein
• Wt. abl gene shuttles between nucleus and cytoplasm
• Activates tyrosine kinase
• Phosphorylates many substrates
• Can transform in hemopoietic cells
Protects hematopoietic cells from apoptosis
How is the function of ABL-BCR effect abl-bcr fusion to activate Tyrosine kinase
- In normal BCR is presented in the cytoplasm
- And in the nucleus there is low levels of ABL proteins resulting in low kinase activity
- In leukaemia patients, BCR and ABL are joined in the cytoplasm for kinase activity
What does it means by ph + in ALL
Worst outcome for children’s
DFS(disease free survival) is 49% at 5yold if wbc at diagnose sis <50,000
DFS 20% at 5yold is wbc is >100,000
What are the treatments of ph + ALL
• Bone marrow transplantation
What is STI 571
- BCR-ABL; inhibitor
- Daily oral therapy
- Given to patients in chronic phase
Less serve side effects
What is follicular lymphomas
• Mutation is t(14,18) (q32,q31) • Types of non Hodgkin lymphoma disease • Bcl-1 is on chromosomes 18 • Which is a regulator of apoptosis Ig heavy chain on chromosomes 14
Although mantle cell lymphoma, CLL/SLL follicular lymphoma, and marginal zone lymphoma may all be comprised of small B cells, mantle cell lymphoma has a more aggressive course. This clinical behavior is thought to be due to which of the following
overexpression of cyclin D1.
•
A pharmaceutical company approaches you for advice. They have developed a new drug that decreases bcl-2 protein synthesis and that, in combination with standard chemotherapy, shows promising results in follicular lymphoma. They would like to use it in other malignancies. Based on the mechanism of action of the drug and the molecular basis and pathophysiology of the diseases, which of the following would be the next best candidate malignancy to test to drug on?
CLL/small lymphocytic lymphoma (SLL), del 13q12 subset
What is T cell lymphomas
• Translocation often involves in T cell cell receptor genes
a rare type of cancer that begins in white blood cells called T cells (T lymphocytes)
Alpha and s chain on 14q11-14
Beta chain on 14q32-36
Gamma chain on 7p15
There are many orter oncogenes such as Lyll and transcription factors families
