Chapter 10: The etiology and genetics of hematological malignancy Flashcards
What genetic conditions are associated with hematological malignancies?
(1) Down’s syndrome
(2) Bloom’s syndrome
(3) Fanconi’s anemia
(4) ataxia telangiectasia
(5) Kleinfelter’s syndrome
(6) Wiskott-Aldrich syndrome
What chemical is commonly linked with hypoplasia, dysplasia, and chromosome abnormalities of the bone marrow?
Benzene
What antineoplastic drugs can also cause hematological malignancy?
The alkylating agents predispose to AML. Etoposide is also associated with the development of secondary malignancies.
What happened to survivors of the atom bomb in Japan?
They suffered from increased incidences of all types of leukemia.
What role does infection play in the development of Acute lymphoblastic leukemia?
Children with the TEL-AML1 translocation who are exposed to a variety of normal childhood infections seem to have lower incidence second hit development of ALL.
With which malignancies is human T cell lymphotropic virus associated?
HTLV is associated with adult t cell leukemia and lymphoma.
What virus is associated with Burkitt’s lymphoma?
EBV is associated with african burkitts lymphoma. EBV also causes post transplant lymphoproliferative disease (PTLD).
With which malignancies is HIV associated?
Lymphomas are often associated with HIV
With what malignancies is kaposi’s sarcoma herpes virus associated.
KSHV is associated with Kaposi’s sarcoma and primary effusion lymphoma.
What malignancy is associated with Helicobacter Pylori infection?
Gastric mucosa B cell lymphoma (MALT)
What genetic feature of hematological malignancies most differentiates them from solid tumors?
The high frequency of chromosomal translocations in hematological malignancies
What is the Philadelphia chromosome?
The philadelphia chromosome is a t(9,22) translocation that is linked to chronic myeloid leukemia and some cases of ALL.
What mutation of the retinoic acid receptor is linked to hematologic malignancies?
t(15; 17) translocation is linked to AML M3. The PML gene on chromosome 15 is fused to the retinoic acid receptor gene on chromosome 17.
How does t(15, 17) cause AML M3?
The PML-RAR fusion gene binds to its normal substrates PML and RXR preventing their normal function. This results in arrest of differentiation
How can AML M3 be successfully treated?
High doses of all trans retinoic acid will stimlulate differentiation in abnormal promyelocytes. But only those with t(15; 17)
What is core binding factor (CBF)?
CBF is a transcription factor that regulates the expression of genes such as IL-3, and GM-CSF.
What three CBF translocations are linked to leukemias?
(1) t(8; 21) CBF-alpha (AML1) is translocated to 8.
(2) inv(16) CBF-beta is fused to MYH11 gene
(3) t(12; 21) linked to pre B ALL
How do MYC rearrangements lead to hematologic malignancies?
The MYC oncogene is translocated to a location under the control of an immunoglobulin regulator. This leads to MYC overexpression. t(8; 14). Burkitt’s lymphoma and B-ALL are linked to this mutation.
How does BCL-2 translocation lead to malignancy?
t(14; 18) BCL-2 translocation leads to the overexpression of BCL-2 which suppresses apoptosis. This is found in 85% of follicular lymphomas.
For what is PCR particularly useful in detecting in hematologic malignancies?
PCR can detect very small amounts of abnormal DNA. Therefore it is very good for detecting residual disease.
For what are microarrays particularly useful for determining in hematological malignancies?
microarrays are not as sensitive as PCR, but they can help differentiates types and subtypes of tumors by determining expression patterns.
How can flow cytometry detect malignant cells in a mixed population?
Flow cytometry can detect cell phenotype. B cell tumor populations tend to be monoclonal and therefore express only kappa or lambda light chains. Alterations of the normal kappa:lambda ratios is indicative of monoclonal expansion.
How does genetic information aid the management of hematologic malignancy?
Genotyping of hematologic malignancies can aid treatment because different subtypes react differently to various therapies.
What are the methods for determining residual disease in decreasing order of sensitivity?
(1) PCR
(2) Flourescence activated cell sorting (flow cytometry)
(3) Southern blot
(4) Cytogenetic analysis.
