KEGG   PATHWAY: ptr05220
ptr05220                    Pathway                                

Chronic myeloid leukemia - Pan troglodytes (chimpanzee)
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
ptr05220  Chronic myeloid leukemia

Pan troglodytes (chimpanzee) [GN:ptr]
458694  BCR; breakpoint cluster region protein isoform X1 [KO:K08878] [EC:]
107976801  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:]
747142  CRK; adapter molecule crk isoform X1 [KO:K04438]
107970369  CRKL; crk-like protein [KO:K04438]
451690  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:]
460858  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
457922  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
471079  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
456565  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
461836  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
455855  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
456035  AKT2; RAC-beta serine/threonine-protein kinase isoform X4 [KO:K04456] [EC:]
740898  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100609583  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
100615623  BAD; bcl2-associated agonist of cell death [KO:K02158]
458156  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
450673  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:]
472749  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:]
100610002  NF-kappa-B essential modulator [KO:K07210]
100609537  IKBKG; LOW QUALITY PROTEIN: NF-kappa-B essential modulator [KO:K07210]
467426  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
461406  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580]
466665  RELA; transcription factor p65 [KO:K04735]
742141  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:]
455214  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
466947  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
737245  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
748918  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
748225  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:]
459171  SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]
452897  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
466302  HRAS; GTPase HRas isoform X1 [KO:K02833]
473387  KRAS; GTPase KRas isoform X1 [KO:K07827]
742713  NRAS; GTPase NRas [KO:K07828]
460182  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:]
100614256  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
463781  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:]
450188  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
456390  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
454037  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
458680  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
457351  SHC1; SHC-transforming protein 1 isoform X7 [KO:K06279]
749831  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
450176  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
453414  SHC4; SHC-transforming protein 4 [KO:K17449]
464393  MYC; myc proto-oncogene protein [KO:K04377]
454681  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
454679  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
465021  CDKN2A; cyclin-dependent kinase inhibitor 2A [KO:K06621]
104001067  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
747442  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
452025  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
746968  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:]
452715  RB1; retinoblastoma-associated protein isoform X2 [KO:K06618]
107969994  E2F1; transcription factor E2F1 [KO:K17454]
469153  E2F2; transcription factor E2F2 isoform X2 [KO:K09389]
471865  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
464585  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
744311  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
456929  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X2 [KO:K04402]
747093  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
462616  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
451165  DDB2; DNA damage-binding protein 2 isoform X2 [KO:K10140]
461803  POLK; DNA polymerase kappa isoform X3 [KO:K03511] [EC:]
456060  TGFB1; transforming growth factor beta-1 isoform X2 [KO:K13375]
457742  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
453054  TGFB3; transforming growth factor beta-3 isoform X1 [KO:K13377]
472992  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:]
460243  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:]
748161  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
468537  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
460837  MECOM; MDS1 and EVI1 complex locus protein EVI1 isoform X7 [KO:K04462] [EC:]
101058316  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
450810  CTBP2; C-terminal-binding protein 2 isoform X1 [KO:K04496]
738792  CTBP1; C-terminal-binding protein 1 isoform X3 [KO:K04496]
748850  histone deacetylase 1 isoform X1 [KO:K06067] [EC:]
462950  HDAC2; histone deacetylase 2 isoform X2 [KO:K06067] [EC:]
107966150  HDAC1; histone deacetylase 1 isoform X3 [KO:K06067] [EC:]
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Ren R.
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Nat Rev Cancer 5:172-83 (2005)
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.
Blood 103:4010-22 (2004)
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)
Mitani K.
Molecular mechanisms of leukemogenesis by AML1/EVI-1.
Oncogene 23:4263-9 (2004)
Dong M, Blobe GC.
Role of transforming growth factor-beta in hematologic malignancies.
Blood 107:4589-96 (2006)
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)
Baldwin AS.
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB.
J Clin Invest 107:241-6 (2001)
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)
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)
ptr04010  MAPK signaling pathway
ptr04110  Cell cycle
ptr04115  p53 signaling pathway
ptr04151  PI3K-Akt signaling pathway
ptr04210  Apoptosis
ptr04350  TGF-beta signaling pathway
ptr04640  Hematopoietic cell lineage
KO pathway

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