KEGG   PATHWAY: pon05220
Entry
pon05220                    Pathway                                

Name
Chronic myeloid leukemia - Pongo abelii (Sumatran orangutan)
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 types
Pathway map
pon05220  Chronic myeloid leukemia
pon05220

Organism
Pongo abelii (Sumatran orangutan) [GN:pon]
Gene
100431481  BCR; breakpoint cluster region protein [KO:K08878] [EC:2.7.11.1]
100453216  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
100452410  CRK; adapter molecule crk isoform X1 [KO:K04438]
100443298  CRKL; crk-like protein [KO:K04438]
100462634  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
100432846  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100453779  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103889133  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100174298  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100173589  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100437617  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100454279  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100448114  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100442100  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100454097  BAD; bcl2-associated agonist of cell death [KO:K02158]
100453051  BCL2L1; bcl-2-like protein 1 [KO:K04570]
100174735  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
100440586  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X3 [KO:K07209] [EC:2.7.11.10]
100449496  IKBKG; NF-kappa-B essential modulator isoform X5 [KO:K07210]
100459445  NF-kappa-B inhibitor alpha [KO:K04734]
100461595  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100456049  RELA; transcription factor p65 [KO:K04735]
100171532  MDM2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
100435218  TP53; cellular tumor antigen p53 [KO:K04451]
100449905  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100173972  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100457376  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
100440983  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
100434331  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100458733  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100459427  HRAS; GTPase HRas [KO:K02833]
100462513  KRAS; GTPase KRas isoform X1 [KO:K07827]
100174317  NRAS; GTPase NRas precursor [KO:K07828]
100173732  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
100431871  ARAF; serine/threonine-protein kinase A-Raf isoform X4 [KO:K08845] [EC:2.7.11.1]
100442288  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100446021  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100450988  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100169740  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100431824  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100173225  SHC1; SHC-transforming protein 1 [KO:K06279]
100445042  SHC2; SHC-transforming protein 2 [KO:K17447]
100462011  SHC3; SHC-transforming protein 3 [KO:K17448]
100431574  SHC4; SHC-transforming protein 4 [KO:K17449]
100456735  MYC; myc proto-oncogene protein [KO:K04377]
100461695  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
100462537  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
100461015  cyclin-dependent kinase inhibitor 2A [KO:K06621]
100453682  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100171625  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100443314  CDK4; cyclin-dependent kinase 4 isoform X2 [KO:K02089] [EC:2.7.11.22]
100454924  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
100462155  RB1; retinoblastoma-associated protein [KO:K06618]
100435851  E2F1; transcription factor E2F1 [KO:K17454]
100458002  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100448297  E2F3; transcription factor E2F3 isoform X3 [KO:K06620]
100436665  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100452809  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100456437  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100450682  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
100460189  bcl-2 homologous antagonist/killer [KO:K14021]
100432001  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
100454099  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
100443121  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
100459982  TGFB1; transforming growth factor beta-1 [KO:K13375]
100461291  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
100433208  TGFB3; transforming growth factor beta-3 [KO:K13377]
100450864  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:2.7.11.30]
100459236  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100448249  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100439171  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100431606  MECOM; MDS1 and EVI1 complex locus protein EVI1 [KO:K04462] [EC:2.1.1.367]
100449725  RUNX1; LOW QUALITY PROTEIN: runt-related transcription factor 1 [KO:K08367]
100461333  CTBP1; C-terminal-binding protein 1 isoform X2 [KO:K04496]
100452123  CTBP2; C-terminal-binding protein 2 isoform X1 [KO:K04496]
100172663  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
100294534  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
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
Related
pathway
pon04010  MAPK signaling pathway
pon04110  Cell cycle
pon04115  p53 signaling pathway
pon04151  PI3K-Akt signaling pathway
pon04210  Apoptosis
pon04350  TGF-beta signaling pathway
pon04640  Hematopoietic cell lineage
KO pathway
ko05220   
LinkDB

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