Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. 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.

Human Diseases; Cancer: specific types
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Cricetulus griseus (Chinese hamster) [GN:cge]

PMID:15719031

Ren R.

Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.

Nat Rev Cancer 5:172-83 (2005)
DOI:10.1038/nrc1567

PMID:11071626

Deininger MW, Goldman JM, Melo JV.

The molecular biology of chronic myeloid leukemia.

Blood 96:3343-56 (2000)

PMID:14982876

Calabretta B, Perrotti D.

The biology of CML blast crisis.

Blood 103:4010-22 (2004)
DOI:10.1182/blood-2003-12-4111

PMID:10403855

Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM.

The biology of chronic myeloid leukemia.

N Engl J Med 341:164-72 (1999)
DOI:10.1056/NEJM199907153410306

PMID:15156182

Mitani K.

Molecular mechanisms of leukemogenesis by AML1/EVI-1.

Oncogene 23:4263-9 (2004)
DOI:10.1038/sj.onc.1207777

PMID:16484590

Dong M, Blobe GC.

Role of transforming growth factor-beta in hematologic malignancies.

Blood 107:4589-96 (2006)
DOI:10.1182/blood-2005-10-4169

PMID:9834202

Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y, Hirai H.

The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells.

Blood 92:4003-12 (1998)

PMID:12801837

Brusa G, Benvenuti M, Mazzacurati L, Mancini M, Pattacini L, Martinelli G, Barbieri E, Greenberger JS, Baccarani M, Santucci MA.

p53 loss of function enhances genomic instability and accelerates clonal evolution of murine myeloid progenitors expressing the p(210)BCR-ABL tyrosine kinase.

Haematologica 88:622-30 (2003)

PMID:11160144

Baldwin AS.

Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB.

J Clin Invest 107:241-6 (2001)
DOI:10.1172/JCI11991

PMID:12244301

Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL.

PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.

Nat Med 8:1145-52 (2002)
DOI:10.1038/nm759

PMID:22286129

Hantschel O, Warsch W, Eckelhart E, Kaupe I, Grebien F, Wagner KU, Superti-Furga G, Sexl V

BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia.

Nat Chem Biol 8:285-93 (2012)
DOI:10.1038/nchembio.775