KEGG   PATHWAY: biu05220
biu05220                    Pathway                                

Chronic myeloid leukemia - Bos indicus (zebu cattle)
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
biu05220  Chronic myeloid leukemia

Bos indicus (zebu cattle) [GN:biu]
109571416  BCR; breakpoint cluster region protein [KO:K08878] [EC:]
109566554  ABL1; tyrosine-protein kinase ABL1 [KO:K06619] [EC:]
109570977  CRKL; crk-like protein [KO:K04438]
109573847  CRK; adapter molecule crk isoform X1 [KO:K04438]
109568806  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:]
109559805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
109570415  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
109557823  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
109574805  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
109561418  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109556345  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109572496  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
109570286  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
109554386  BAD; bcl2-associated agonist of cell death [KO:K02158]
109567345  BCL2L1; bcl-2-like protein 1 [KO:K04570]
109565507  bcl-2-like protein 1 [KO:K04570]
109553086  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:]
109553353  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:]
109575581  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
109560296  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
109554392  RELA; transcription factor p65 [KO:K04735]
109558399  MDM2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:]
109574238  TP53; cellular tumor antigen p53 [KO:K04451]
109559641  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
109574040  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
109554314  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
109570168  tyrosine-protein phosphatase non-receptor type 11-like [KO:K07293] [EC:]
109570927  PTPN11; tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:]
109566002  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
109564346  SOS2; son of sevenless homolog 2 [KO:K03099]
109560940  GTPase HRas-like [KO:K02833]
109559581  KRAS; GTPase KRas isoform X1 [KO:K07827]
109555890  NRAS; GTPase NRas [KO:K07828]
109576053  RAF1; LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
109555027  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
109557698  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
109564697  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:]
109561751  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
109578667  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
109570973  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
109553931  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
109561056  SHC2; SHC-transforming protein 2 [KO:K17447]
109562580  SHC3; SHC-transforming protein 3 [KO:K17448]
109565147  SHC4; SHC-transforming protein 4 [KO:K17449]
109568594  MYC; myc proto-oncogene protein [KO:K04377]
109574089  signal transducer and activator of transcription 5A-like [KO:K11223]
109573773  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
109562627  tumor suppressor ARF-like isoform X1 [KO:K06621]
109577247  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625]
109554439  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
109559308  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
109558203  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:]
109566987  RB1; retinoblastoma-associated protein [KO:K06618]
109567683  E2F1; transcription factor E2F1 [KO:K17454]
109576116  E2F2; transcription factor E2F2 [KO:K09389]
109577245  E2F3; transcription factor E2F3 [KO:K06620]
109561788  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
109556176  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
109563283  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
109571977  apoptosis regulator BAX [KO:K02159]
109571778  BAX; apoptosis regulator BAX [KO:K02159]
109577301  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
109569541  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
109564642  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:]
109572866  TGFB1; transforming growth factor beta-1 [KO:K13375]
109570509  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
109565371  TGFB3; transforming growth factor beta-3 [KO:K13377]
109563078  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:]
109576148  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:]
109564704  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
109577834  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
109558403  MECOM; MDS1 and EVI1 complex locus protein EVI1 isoform X1 [KO:K04462] [EC:]
109561422  RUNX1; runt-related transcription factor 1 [KO:K08367]
109579110  CTBP2; C-terminal-binding protein 2 isoform X1 [KO:K04496]
109560714  CTBP1; C-terminal-binding protein 1 [KO:K04496]
109572356  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:]
109563503  HDAC2; histone deacetylase 2 [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)
biu04010  MAPK signaling pathway
biu04110  Cell cycle
biu04115  p53 signaling pathway
biu04151  PI3K-Akt signaling pathway
biu04210  Apoptosis
biu04350  TGF-beta signaling pathway
biu04640  Hematopoietic cell lineage
KO pathway

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