KEGG   PATHWAY: hsa05220Help
Entry
hsa05220                    Pathway                                

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
09160 Human Diseases; 09161 Cancers
BRITE hierarchy
Pathway map
hsa05220  Chronic myeloid leukemia
hsa05220

Ortholog table
Network
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 (CML)
Drug
D01441  Imatinib mesylate (USAN)
D03252  Bosutinib (USAN)
D03658  Dasatinib (JAN/INN)
D06413  Nilotinib hydrochloride hydrate (JAN)
D06414  Dasatinib (USAN)
D08066  Imatinib (INN)
D08953  Nilotinib (USAN/INN)
D08956  Omacetaxine mepesuccinate (USAN)
D09728  Bosutinib hydrate (JAN)
D09950  Ponatinib (USAN/INN)
D09951  Ponatinib hydrochloride (JAN/USAN)
D10202  Bafetinib (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
613  BCR; BCR, RhoGEF and GTPase activating protein [KO:K08878] [EC:2.7.11.1]
25  ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
867  CBL; Cbl proto-oncogene [KO:K04707] [EC:2.3.2.27]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
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]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
598  BCL2L1; BCL2 like 1 [KO:K04570]
1147  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
4193  MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
7157  TP53; tumor protein p53 [KO:K04451]
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]
5781  PTPN11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
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]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
369  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
6464  SHC1; SHC adaptor protein 1 [KO:K06279]
25759  SHC2; SHC adaptor protein 2 [KO:K17447]
53358  SHC3; SHC adaptor protein 3 [KO:K17448]
399694  SHC4; SHC adaptor protein 4 [KO:K17449]
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]
595  CCND1; cyclin D1 [KO:K04503]
1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
1021  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
5925  RB1; RB transcriptional corepressor 1 [KO:K06618]
1869  E2F1; E2F transcription factor 1 [KO:K17454]
1870  E2F2; E2F transcription factor 2 [KO:K09389]
1871  E2F3; E2F transcription factor 3 [KO:K06620]
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]
51426  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
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]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
7048  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
4089  SMAD4; SMAD family member 4 [KO:K04501]
2122  MECOM; MDS1 and EVI1 complex locus [KO:K04462]
861  RUNX1; runt related transcription factor 1 [KO:K08367]
1487  CTBP1; C-terminal binding protein 1 [KO:K04496]
1488  CTBP2; C-terminal binding protein 2 [KO:K04496]
3065  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
3066  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
4088  SMAD3; SMAD family member 3 [KO:K04500]
Compound
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Ren R.
  Title
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
  Journal
Nat Rev Cancer 5:172-83 (2005)
DOI:10.1038/nrc1567
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
Blood 103:4010-22 (2004)
DOI:10.1182/blood-2003-12-4111
Reference
  Authors
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM.
  Title
The biology of chronic myeloid leukemia.
  Journal
N Engl J Med 341:164-72 (1999)
DOI:10.1056/NEJM199907153410306
Reference
  Authors
Mitani K.
  Title
Molecular mechanisms of leukemogenesis by AML1/EVI-1.
  Journal
Oncogene 23:4263-9 (2004)
DOI:10.1038/sj.onc.1207777
Reference
  Authors
Dong M, Blobe GC.
  Title
Role of transforming growth factor-beta in hematologic malignancies.
  Journal
Blood 107:4589-96 (2006)
DOI:10.1182/blood-2005-10-4169
Reference
PMID:9834202
  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
J Clin Invest 107:241-6 (2001)
DOI:10.1172/JCI11991
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
Nat Med 8:1145-52 (2002)
DOI:10.1038/nm759
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
Nat Chem Biol 8:285-93 (2012)
DOI:10.1038/nchembio.775
KO pathway
ko05220   

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