KEGG   PATHWAY: cfr05220
Entry
cfr05220                    Pathway                                

Name
Chronic myeloid leukemia - Camelus ferus (Wild Bactrian camel)
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
cfr05220  Chronic myeloid leukemia
cfr05220

Organism
Camelus ferus (Wild Bactrian camel) [GN:cfr]
Gene
102509438  BCR; breakpoint cluster region protein isoform X1 [KO:K08878] [EC:2.7.11.1]
102519310  ABL1; tyrosine-protein kinase ABL1 isoform X2 [KO:K06619] [EC:2.7.10.2]
102516584  CRKL; crk-like protein [KO:K04438]
102511476  CRK; adapter molecule crk isoform X1 [KO:K04438]
102504124  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
102523502  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102518643  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102519994  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102513205  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
102505690  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102520923  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102503460  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102515350  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102519101  RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
106729149  AKT1; LOW QUALITY PROTEIN: RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102523295  BAD; bcl2-associated agonist of cell death isoform X2 [KO:K02158]
102504996  BCL2L1; bcl-2-like protein 1 isoform X2 [KO:K04570]
102503497  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
102508142  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102519782  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
102519409  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
102505905  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102506204  RELA; transcription factor p65 isoform X1 [KO:K04735]
102522420  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
102524476  TP53; cellular tumor antigen p53 [KO:K04451]
102518884  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
102515306  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
102518228  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
102523889  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
102507247  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102517014  SOS2; son of sevenless homolog 2 [KO:K03099]
102524334  HRAS; GTPase HRas isoform X1 [KO:K02833]
102516372  KRAS; GTPase KRas isoform X1 [KO:K07827]
102509562  NRAS; GTPase NRas [KO:K07828]
102517521  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102506774  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102524100  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
102515937  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102511209  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
102517586  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102521659  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102524489  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102506382  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
102508169  SHC3; SHC-transforming protein 3 [KO:K17448]
102517753  SHC4; SHC-transforming protein 4 [KO:K17449]
102511086  MYC; myc proto-oncogene protein [KO:K04377]
102520794  signal transducer and activator of transcription 5A [KO:K11223]
102511001  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
102509404  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
102518309  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
102522300  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
102520456  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
102516870  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
102517851  E2F1; transcription factor E2F1 [KO:K17454]
102515523  E2F2; transcription factor E2F2 [KO:K09389]
102513737  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
102516207  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102508482  GADD45A; LOW QUALITY PROTEIN: growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
116660720  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102512073  ferritin light chain isoform X1 [KO:K02159]
102513729  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
102523860  DDB2; DNA damage-binding protein 2 isoform X4 [KO:K10140]
102507560  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
102509937  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
102505811  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
102517948  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
102522485  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
102509744  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
102507868  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
102519252  MECOM; histone-lysine N-methyltransferase MECOM isoform X2 [KO:K04462] [EC:2.1.1.367]
102521748  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
102508242  CTBP1; C-terminal-binding protein 1 isoform X1 [KO:K04496]
102519579  CTBP2; LOW QUALITY PROTEIN: C-terminal-binding protein 2 [KO:K04496]
102508320  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
102504100  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
cfr04010  MAPK signaling pathway
cfr04110  Cell cycle
cfr04115  p53 signaling pathway
cfr04151  PI3K-Akt signaling pathway
cfr04210  Apoptosis
cfr04350  TGF-beta signaling pathway
cfr04640  Hematopoietic cell lineage
KO pathway
ko05220   
LinkDB

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