Chapter 10: The etiology and genetics of hematological malignancy

Question 1

What genetic conditions are associated with hematological malignancies?

Answer 1

(1) Down’s syndrome
(2) Bloom’s syndrome
(3) Fanconi’s anemia
(4) ataxia telangiectasia
(5) Kleinfelter’s syndrome
(6) Wiskott-Aldrich syndrome

Question 2

What chemical is commonly linked with hypoplasia, dysplasia, and chromosome abnormalities of the bone marrow?

Answer 2

Benzene

Question 3

What antineoplastic drugs can also cause hematological malignancy?

Answer 3

The alkylating agents predispose to AML. Etoposide is also associated with the development of secondary malignancies.

Question 4

What happened to survivors of the atom bomb in Japan?

Answer 4

They suffered from increased incidences of all types of leukemia.

Question 5

What role does infection play in the development of Acute lymphoblastic leukemia?

Answer 5

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.

Question 6

With which malignancies is human T cell lymphotropic virus associated?

Answer 6

HTLV is associated with adult t cell leukemia and lymphoma.

Question 7

What virus is associated with Burkitt’s lymphoma?

Answer 7

EBV is associated with african burkitts lymphoma. EBV also causes post transplant lymphoproliferative disease (PTLD).

Question 8

With which malignancies is HIV associated?

Answer 8

Lymphomas are often associated with HIV

Question 9

With what malignancies is kaposi’s sarcoma herpes virus associated.

Answer 9

KSHV is associated with Kaposi’s sarcoma and primary effusion lymphoma.

Question 10

What malignancy is associated with Helicobacter Pylori infection?

Answer 10

Gastric mucosa B cell lymphoma (MALT)

Question 11

What genetic feature of hematological malignancies most differentiates them from solid tumors?

Answer 11

The high frequency of chromosomal translocations in hematological malignancies

Question 12

What is the Philadelphia chromosome?

Answer 12

The philadelphia chromosome is a t(9,22) translocation that is linked to chronic myeloid leukemia and some cases of ALL.

Question 13

What mutation of the retinoic acid receptor is linked to hematologic malignancies?

Answer 13

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.

Question 14

How does t(15, 17) cause AML M3?

Answer 14

The PML-RAR fusion gene binds to its normal substrates PML and RXR preventing their normal function. This results in arrest of differentiation

Question 15

How can AML M3 be successfully treated?

Answer 15

High doses of all trans retinoic acid will stimlulate differentiation in abnormal promyelocytes. But only those with t(15; 17)

Question 16

What is core binding factor (CBF)?

Answer 16

CBF is a transcription factor that regulates the expression of genes such as IL-3, and GM-CSF.

Question 17

What three CBF translocations are linked to leukemias?

Answer 17

(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

Question 18

How do MYC rearrangements lead to hematologic malignancies?

Answer 18

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.

Question 19

How does BCL-2 translocation lead to malignancy?

Answer 19

t(14; 18) BCL-2 translocation leads to the overexpression of BCL-2 which suppresses apoptosis. This is found in 85% of follicular lymphomas.

Question 20

For what is PCR particularly useful in detecting in hematologic malignancies?

Answer 20

PCR can detect very small amounts of abnormal DNA. Therefore it is very good for detecting residual disease.

Question 21

For what are microarrays particularly useful for determining in hematological malignancies?

Answer 21

microarrays are not as sensitive as PCR, but they can help differentiates types and subtypes of tumors by determining expression patterns.

Question 22

How can flow cytometry detect malignant cells in a mixed population?

Answer 22

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.

Question 23

How does genetic information aid the management of hematologic malignancy?

Answer 23

Genotyping of hematologic malignancies can aid treatment because different subtypes react differently to various therapies.

Question 24

What are the methods for determining residual disease in decreasing order of sensitivity?

Answer 24

(1) PCR
(2) Flourescence activated cell sorting (flow cytometry)
(3) Southern blot
(4) Cytogenetic analysis.

Question 25

What markers are used to detect blasts and granulocyte precursors in flow cytometry?

Answer 25

CD 34 is used to detect blasts

CD33 is used for granulocytes.

Question 26

What are acute hematological malignancies?

Answer 26

?

Question 27

What are chronic hematologic malignancies?

Answer 27

?

Question 28

What is more clinically useful genotyping or immunophenotyping?

Answer 28

Genotyping is more clinically useful.