Chronic myeloid leukemia (CML)

Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoetic cell lineages are involved in the process of clonal proliferation and differentiation. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22.  The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1. Additional chromosome translocations are also observed,such as t(3;21)(q26;q22), which generates AML1-EVI1.

Cancer

BCR-ABL (translocation) [HSA:613 25] [KO:K08878 K06619]
EVI1 (overexpression) [HSA:2122] [KO:K04462]
AML1 (translocation) [HSA:861] [KO:K08367]
p16/INK4A (mutation) [HSA:1029] [KO:K06621]
p53 (mutation) [HSA:7157] [KO:K04451]
RB1 (mutation) [HSA:5925] [KO:K06618]

1,3-Butadiene [CPD:C16450]
Rubber industry

BCR-ABL (translocation) [HSA:613 25]
WT1 [HSA:7490]

Imatinib mesylate (Gleevec) [DR:D01441]
Hydroxyurea [DR:D00341]
Interferon-alpha [DR:D00745 D02745 D03305 D04552 D04553]

ICD-O: 9875/3, Tumor type: Chronic myelogenous leukaemia

PMID:15719031 (gene, tumor type)

Ren R.

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PMID:10403855 (gene)

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N Engl J Med 341:164-72 (1999)

PMID:14982876 (gene)

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The biology of CML blast crisis.

Blood 103:4010-22 (2004)

PMID:16155477 (carcinogen)

Graff JJ, Sathiakumar N, Macaluso M, Maldonado G, Matthews R, Delzell E.

Chemical exposures in the synthetic rubber industry and lymphohematopoietic cancer mortality.

J Occup Environ Med 47:916-32 (2005)

PMID:9498905 (carcinogen)

Blair A, Kazerouni N.

Reactive chemicals and cancer.

Cancer Causes Control 8:473-90 (1997)

PMID:16873420 (carcinogen)

Alder N, Fenty J, Warren F, Sutton AJ, Rushton L, Jones DR, Abrams KR.

Meta-analysis of mortality and cancer incidence among workers in the synthetic rubber-producing industry.

Am J Epidemiol 164:405-20 (2006)

PMID:16299089 (carcinogen)

Sathiakumar N, Graff J, Macaluso M, Maldonado G, Matthews R, Delzell E.

An updated study of mortality among North American synthetic rubber industry workers.

Occup Environ Med 62:822-9 (2005)

PMID:15265366 (marker)

Chen ZX, Kaeda J, Saunders S, Goldman JM.

Expression patterns of WT-1 and Bcr-Abl measured by TaqMan quantitative real-time RT-PCR during follow-up of leukemia patients with the Ph chromosome.

Chin Med J (Engl) 117:968-71 (2004)

PMID:15661271 (marker)

Na IK, Kreuzer KA, Lupberger J, Dorken B, le Coutre P.

Quantitative RT-PCR of Wilms tumor gene transcripts (WT1) for the molecular monitoring of patients with accelerated phase bcr/abl + CML.

Leuk Res 29:343-5 (2005)

PMID:11529849 (marker)

Kreuzer KA, Saborowski A, Lupberger J, Appelt C, Na IK, le Coutre P, Schmidt CA.

Fluorescent 5'-exonuclease assay for the absolute quantification of Wilms' tumour gene (WT1) mRNA: implications for monitoring human leukaemias.

Br J Haematol 114:313-8 (2001)

(drug)

McPhee SJ, Papadakis MA, Tierney LM (ed).

Current Medical Diagnosis & Treatment 2007, Forty-Sixth Edition

The McGraw-Hill Companies, Inc. (2007)