CML case

Question 1

Reciprocal translocation occurs where in the BCR-ABL protein and forms what?

Answer 1

22 and 9

Fusion gene

Question 2

BCR (breakpoint cluster gene)

Answer 2

Housekeeping gene that’s always on

Question 3

ABL (Abelson leukemia)

Answer 3

Proto-oncogene that codes for a non-receptor TK found in the cytoplasm and nucleus

Question 4

What must happen for ABL to be an oncogene?

Answer 4

ABL binds to BCR

Question 5

What occurs in CML resulting in BCR-ABL fusion?

Answer 5

Chimeric protein w/ strong and constitutive TK activity

Question 6

What proto-oncogenic pathways that compound the production of cancer cells?

Answer 6

RAS, PLK3, JAK/STAT

Question 7

Imatinib (Gleevec)

Answer 7

Competitive inhibitor

Block binding of ATP to BCR-ABL tyrosine kinase, inhibiting it’s activity

Question 8

What happen to the onocgene activity if TK is blocked?

Answer 8

Substrate required for BCR-ABL function cannot be phosphorylated and cellular events don’t occur

Question 9

What are the side effects to imatinib?

Answer 9

Hematological - neutropenia, thrombocytopenia, anemia

Non-hematological - superficial edema, nausea, headache

Question 10

Imatinib resistance

Answer 10

Mutation so that the cell blocks enzymatic site so drug cannot bind
Mutation leads to active receptor T315I

Question 11

Ponatinib

Answer 11

Only drug that is effective against T315I mutation
Currently inhibits all mutated &
unmutated forms of BCR-ABL

Question 12

Omacetaxine mepesuccinate

Answer 12

Binds 80S ribosome, no chain elongation

Question 13

Busulfan

Answer 13

Alkylating agent

Bone marrow depression (stem cells)

Question 14

IFN α-2b

Answer 14

Inhibits cell proliferation, interferes w/ oncogene expression, enhances immune activities
(↑macrophage phagocytosis & augments T cell cytotoxicity)

Question 15

Cyclophosphamide

Answer 15

Alkylating agent (nitrogen mustard): puts alkyl group on guanine – crosslinking interferes w/ DNA 
can’t unwind, replicate, or transcribe
Cardiotoxicity, hemorrhagic cystitis, hematuria (co-administer w/ MESNA to prevent bladder burn)

Question 16

Mechlorethamine

Answer 16

Alkylating agent (nitrogen mustard): puts alkyl group on guanine – crosslinking interferes w/ DNA
Can’t unwind, replicate, or transcribe
Unstable (most reactive)

Question 17

Cytarabine

Answer 17

2’-deoxycytidine analog; no base rotation, no chain elongation, DNA polymerase inhibition
Bone marrow depression

Question 18

What are some common reaction in graft vs host response

Answer 18

Diarrhea, erythema, dispigmentation, weight loss, malaise, fever, joint pains
Eventual death

Question 19

What does graft vs host response do?

Answer 19

Infections due to immunosuppressive regimens – viral, bacterial fungal

Question 20

How is graft vs host disease minimized?

Answer 20

Careful patient preparation & best ABO-compatible HLA match

Multi-tiered approach to immunosuppressive drug therapy

Question 21

Methotrexate

Answer 21

Folic acid antagonist
Azotemia, systemic bacterial infection of blood or tissues, GI bleeding, ↓WBC & platelets,
inflammation of mucosal surfaces

Question 22

Cyclosporine

Answer 22

Blocks transcription of cytokine genes in activated T cells

Nephrotoxicity, hypertension

Question 23

Tacrolimus

Answer 23

Binds FK506; complex inhibits calcineurin phosphatase
Inhibits Ca2+ dependent events (e.g. degranulation, apoptosis)
Nephrotoxicity, hyperglycemia, diabetes, neurotoxicity