Chronic myeloid leukemia - Homo sapiens (human)
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
Pathway map Ortholog table
N00002 BCR-ABL fusion kinase to RAS-ERK signaling pathway
N00048 BCR-ABL fusion kinase to PI3K signaling pathway
N00055 BCR-ABL fusion kinase to Jak-STAT signaling pathway
N00067 Deleted p14(ARF) to p21-cell cycle G1/S
N00070 Mutation-inactivated p16(INK4a) to p16-cell cycle G1/S
N00074 Loss of RB1 to cell cycle G1/S
N00106 AML1-EVI1 fusion to TGF-beta signaling pathway
N00107 EVI-1 overexpression to TGF-beta signaling pathway
N00115 Mutation-inactivated TP53 to transcription
H00004 Chronic myeloid leukemia
D01441 Imatinib mesylate (USAN)
D06413 Nilotinib hydrochloride hydrate (JAN)
D08956 Omacetaxine mepesuccinate (USAN)
D09728 Bosutinib hydrate (JAN)
D09951 Ponatinib hydrochloride (JAN/USAN)
D11404 Asciminib hydrochloride (JAN/USAN)
Homo sapiens (human) [GN:
25 ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO: K06619] [EC: 22.214.171.124]
1398 CRK; CRK proto-oncogene, adaptor protein [KO: K04438]
1399 CRKL; CRK like proto-oncogene, adaptor protein [KO: K04438]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO: K00922] [EC: 126.96.36.199]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO: K00922] [EC: 188.8.131.52]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO: K00922] [EC: 184.108.40.206]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO: K02649]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO: K02649]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO: K02649]
572 BAD; BCL2 associated agonist of cell death [KO: K02158]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO: K04467] [EC: 220.127.116.11]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO: K07210]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO: K02580]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO: K04735]
1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO: K06624]
2885 GRB2; growth factor receptor bound protein 2 [KO: K04364]
9846 GAB2; GRB2 associated binding protein 2 [KO: K08091]
6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO: K03099]
6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO: K03099]
3265 HRAS; HRas proto-oncogene, GTPase [KO: K02833]
3845 KRAS; KRAS proto-oncogene, GTPase [KO: K07827]
4893 NRAS; NRAS proto-oncogene, GTPase [KO: K07828]
4609 MYC; MYC proto-oncogene, bHLH transcription factor [KO: K04377]
6776 STAT5A; signal transducer and activator of transcription 5A [KO: K11223]
6777 STAT5B; signal transducer and activator of transcription 5B [KO: K11224]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO: K06621]
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO: K06625]
5925 RB1; RB transcriptional corepressor 1 [KO: K06618]
1647 GADD45A; growth arrest and DNA damage inducible alpha [KO: K04402]
4616 GADD45B; growth arrest and DNA damage inducible beta [KO: K04402]
10912 GADD45G; growth arrest and DNA damage inducible gamma [KO: K04402]
581 BAX; BCL2 associated X, apoptosis regulator [KO: K02159]
578 BAK1; BCL2 antagonist/killer 1 [KO: K14021]
1643 DDB2; damage specific DNA binding protein 2 [KO: K10140]
7040 TGFB1; transforming growth factor beta 1 [KO: K13375]
7042 TGFB2; transforming growth factor beta 2 [KO: K13376]
7043 TGFB3; transforming growth factor beta 3 [KO: K13377]
861 RUNX1; RUNX family transcription factor 1 [KO: K08367]
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Deininger MW, Goldman JM, Melo JV.
The molecular biology of chronic myeloid leukemia.
Blood 96:3343-56 (2000)
Calabretta B, Perrotti D.
The biology of CML blast crisis.
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM.
The biology of chronic myeloid leukemia.
Molecular mechanisms of leukemogenesis by AML1/EVI-1.
Dong M, Blobe GC.
Role of transforming growth factor-beta in hematologic malignancies.
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)
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)
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB.
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.
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.