KEGG   PATHWAY: pcad05220
Entry
pcad05220                   Pathway                                
Name
Chronic myeloid leukemia - Physeter catodon (sperm whale)
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
pcad05220  Chronic myeloid leukemia
pcad05220

Organism
Physeter catodon (sperm whale) [GN:pcad]
Gene
114485050  breakpoint cluster region protein-like [KO:K08878] [EC:2.7.11.1]
102988541  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
102994214  CRK; adapter molecule crk isoform X1 [KO:K04438]
102990100  CRKL; crk-like protein [KO:K04438]
102994124  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
102986098  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102978952  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102977108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102975555  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102991779  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102991192  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102981524  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102976971  AKT3; RAC-gamma serine/threonine-protein kinase isoform X3 [KO:K04456] [EC:2.7.11.1]
102990087  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102974655  BAD; bcl2-associated agonist of cell death [KO:K02158]
102980439  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
102977668  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X2 [KO:K04467] [EC:2.7.11.10]
102976706  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
114485485  NF-kappa-B essential modulator-like isoform X1 [KO:K07210]
102980964  IKBKG; NF-kappa-B essential modulator [KO:K07210]
102973672  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
102981135  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102974198  RELA; transcription factor p65 isoform X1 [KO:K04735]
102980125  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
102985658  TP53; cellular tumor antigen p53 [KO:K04451]
102981902  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
114483947  growth factor receptor-bound protein 2 [KO:K04364]
102984031  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
102979922  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
102987506  tyrosine-protein phosphatase non-receptor type 11-like isoform X1 [KO:K07293] [EC:3.1.3.48]
102991639  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102981677  LOW QUALITY PROTEIN: son of sevenless homolog 2-like [KO:K03099]
102978925  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
102994715  HRAS; GTPase HRas isoform X2 [KO:K02833]
102977125  KRAS; GTPase KRas isoform X1 [KO:K07827]
102992439  LOW QUALITY PROTEIN: GTPase NRas-like [KO:K07828]
102982641  NRAS; LOW QUALITY PROTEIN: GTPase NRas [KO:K07828]
102987866  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
102974274  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102986916  BRAF; serine/threonine-protein kinase B-raf isoform X3 [KO:K04365] [EC:2.7.11.1]
102992191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102994150  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102984305  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102989074  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102991486  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102974315  SHC2; SHC-transforming protein 2 [KO:K17447]
102977456  SHC3; SHC-transforming protein 3 [KO:K17448]
102988652  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
102988128  MYC; myc proto-oncogene protein [KO:K04377]
102978994  signal transducer and activator of transcription 5A [KO:K11223]
102994339  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
102984840  cyclin-dependent kinase inhibitor 2A-like isoform X3 [KO:K06621]
102995437  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
102996914  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
102985179  CDK4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
102992532  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
102995201  RB1; retinoblastoma-associated protein [KO:K06618]
102993481  E2F1; transcription factor E2F1 [KO:K17454]
102996979  transcription factor E2F2 [KO:K09389]
102976146  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
102974987  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
102993403  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102986518  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102991092  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
102974256  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
102976634  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
102975643  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
102993033  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
102977345  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
102978050  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
102995949  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
102989819  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
102986517  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
102976185  MECOM; histone-lysine N-methyltransferase MECOM isoform X3 [KO:K04462] [EC:2.1.1.367]
102984857  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
102983083  CTBP1; C-terminal-binding protein 1 isoform X1 [KO:K04496] [EC:1.1.1.428]
102985283  CTBP2; C-terminal-binding protein 2 isoform X5 [KO:K04496] [EC:1.1.1.428]
102993806  HDAC2; histone deacetylase 2 isoform X3 [KO:K06067] [EC:3.5.1.98]
102991367  HDAC1; histone deacetylase 1 isoform X1 [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
pcad04010  MAPK signaling pathway
pcad04110  Cell cycle
pcad04115  p53 signaling pathway
pcad04151  PI3K-Akt signaling pathway
pcad04210  Apoptosis
pcad04350  TGF-beta signaling pathway
pcad04640  Hematopoietic cell lineage
KO pathway
ko05220   
LinkDB

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