Entry Name Chronic myeloid leukemia - Homo sapiens (human)
Description 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.
Class Human Diseases; Cancer: specific typesBRITE hierarchy
Pathway map Network Element 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
Disease H00004 Chronic myeloid leukemia
Drug D01441 Imatinib mesylate (USAN)
D06413 Nilotinib hydrochloride hydrate (JAN)
D08956 Omacetaxine mepesuccinate (USAN)
D09728 Bosutinib hydrate (JAN)
D09951 Ponatinib hydrochloride (JAN/USAN)
D10176 Trametinib dimethyl sulfoxide (JAN/USAN)
D11404 Asciminib hydrochloride (JAN/USAN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 1026 CDKN1A; cyclin-dependent kinase inhibitor 1 isoform 1 [KO:K06625 ]
1027 CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624 ]
1029 CDKN2A; cyclin-dependent kinase inhibitor 2A isoform p16INK4a [KO:K06621 ]
10912 GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402 ]
1147 CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform 1 [KO:K04467 ] [EC:2.7.11.10 ]
1398 CRK; adapter molecule crk isoform a [KO:K04438 ]
1643 DDB2; DNA damage-binding protein 2 isoform WT [KO:K10140 ]
1647 GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform 1 [KO:K04402 ]
1871 E2F3; transcription factor E2F3 isoform 1 [KO:K06620 ]
208 AKT2; RAC-beta serine/threonine-protein kinase isoform 1 [KO:K04456 ] [EC:2.7.11.1 ]
25759 SHC2; SHC-transforming protein 2 isoform 1 [KO:K17447 ]
2885 GRB2; growth factor receptor-bound protein 2 isoform 1 [KO:K04364 ]
3551 IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1 [KO:K07209 ] [EC:2.7.11.10 ]
4088 SMAD3; mothers against decapentaplegic homolog 3 isoform 1 [KO:K23605 ]
4089 SMAD4; mothers against decapentaplegic homolog 4 isoform a [KO:K04501 ]
4609 MYC; myc proto-oncogene protein isoform 1 [KO:K04377 ]
4616 GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402 ]
4790 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform 2 proprotein [KO:K02580 ]
4792 NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734 ]
5290 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform 1 [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 1 [KO:K02649 ]
5296 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
5604 MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368 ] [EC:2.7.12.2 ]
5605 MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369 ] [EC:2.7.12.2 ]
572 BAD; bcl2-associated agonist of cell death [KO:K02158 ]
578 BAK1; bcl-2 homologous antagonist/killer [KO:K14021 ]
5781 PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform 1 [KO:K07293 ] [EC:3.1.3.48 ]
581 BAX; apoptosis regulator BAX isoform alpha [KO:K02159 ]
5894 RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform b [KO:K04366 ] [EC:2.7.11.1 ]
5925 RB1; retinoblastoma-associated protein isoform 1 [KO:K06618 ]
595 CCND1; G1/S-specific cyclin-D1 [KO:K04503 ]
5970 RELA; transcription factor p65 isoform 1 [KO:K04735 ]
598 BCL2L1; bcl-2-like protein 1 isoform Bcl-X(L) [KO:K04570 ]
6464 SHC1; SHC-transforming protein 1 isoform 1 [KO:K06279 ]
6654 SOS1; son of sevenless homolog 1 isoform 1 [KO:K03099 ]
6655 SOS2; son of sevenless homolog 2 isoform 1 [KO:K03099 ]
6776 STAT5A; signal transducer and activator of transcription 5A isoform 1 [KO:K11223 ]
6777 STAT5B; signal transducer and activator of transcription 5B [KO:K11224 ]
7040 TGFB1; transforming growth factor beta-1 proprotein preproprotein [KO:K13375 ]
7042 TGFB2; transforming growth factor beta-2 proprotein isoform 2 preproprotein [KO:K13376 ]
7043 TGFB3; transforming growth factor beta-3 proprotein isoform 1 preproprotein [KO:K13377 ]
7157 TP53; cellular tumor antigen p53 isoform a [KO:K04451 ]
8503 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649 ]
8517 IKBKG; NF-kappa-B essential modulator isoform a [KO:K07210 ]
861 RUNX1; runt-related transcription factor 1 isoform AML1b [KO:K08367 ]
9846 GAB2; GRB2-associated-binding protein 2 isoform a [KO:K08091 ]
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Ren R.
Title Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Journal Reference Authors Deininger MW, Goldman JM, Melo JV.
Title The molecular biology of chronic myeloid leukemia.
Journal Blood 96:3343-56 (2000)
Reference Authors Calabretta B, Perrotti D.
Title The biology of CML blast crisis.
Journal Reference Authors Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM.
Title The biology of chronic myeloid leukemia.
Journal Reference Authors Mitani K.
Title Molecular mechanisms of leukemogenesis by AML1/EVI-1.
Journal Reference Authors Dong M, Blobe GC.
Title Role of transforming growth factor-beta in hematologic malignancies.
Journal Reference Authors Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y, Hirai H.
Title The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells.
Journal Blood 92:4003-12 (1998)
Reference Authors Brusa G, Benvenuti M, Mazzacurati L, Mancini M, Pattacini L, Martinelli G, Barbieri E, Greenberger JS, Baccarani M, Santucci MA.
Title p53 loss of function enhances genomic instability and accelerates clonal evolution of murine myeloid progenitors expressing the p(210)BCR-ABL tyrosine kinase.
Journal Haematologica 88:622-30 (2003)
Reference Authors Baldwin AS.
Title Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB.
Journal Reference Authors Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL.
Title PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.
Journal Reference Authors Hantschel O, Warsch W, Eckelhart E, Kaupe I, Grebien F, Wagner KU, Superti-Furga G, Sexl V
Title BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia.
Journal Related KO pathway
