KEGG   PATHWAY: aml05220
aml05220                    Pathway                                

Chronic myeloid leukemia - Ailuropoda melanoleuca (giant panda)
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
aml05220  Chronic myeloid leukemia

Ailuropoda melanoleuca (giant panda) [GN:aml]
100468203  BCR; breakpoint cluster region protein [KO:K08878] [EC:]
100466468  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:]
100466609  CRKL; crk-like protein [KO:K04438]
100467322  CRK; adapter molecule crk isoform X1 [KO:K04438]
100470573  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:]
100463775  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
100479294  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
100479580  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
100475291  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100483828  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100467916  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100468763  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
100480414  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100465793  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100473937  BAD; bcl2-associated agonist of cell death [KO:K02158]
100469922  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
100464675  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:]
100471679  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:]
100470223  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
100466997  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100467906  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100480158  RELA; transcription factor p65 isoform X1 [KO:K04735]
100479481  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:]
100468516  TP53; cellular tumor antigen p53 [KO:K04451]
100467824  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100468916  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100469823  GAB2; GRB2-associated-binding protein 2 isoform X6 [KO:K08091]
100468867  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:]
100471152  LOW QUALITY PROTEIN: tyrosine-protein phosphatase non-receptor type 11-like [KO:K07293] [EC:]
100474396  SOS2; son of sevenless homolog 2 isoform X9 [KO:K03099]
100482526  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100473836  HRAS; GTPase HRas isoform X1 [KO:K02833]
100483919  KRAS; GTPase KRas isoform X1 [KO:K07827]
100464196  NRAS; GTPase NRas [KO:K07828]
100482255  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:]
100475955  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:]
100469346  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
100478039  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
100465700  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
100470035  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
100472388  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
100480856  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100480694  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
100468080  SHC3; SHC-transforming protein 3 [KO:K17448]
100475137  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
100464396  MYC; myc proto-oncogene protein [KO:K04377]
100469683  signal transducer and activator of transcription 5A [KO:K11223]
100479246  signal transducer and activator of transcription 5B [KO:K11224]
100472171  cyclin-dependent kinase inhibitor 2A isoform X3 [KO:K06621]
100484923  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100469787  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
100481236  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
100476389  CDK6; cyclin-dependent kinase 6 isoform X2 [KO:K02091] [EC:]
100477714  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
100475779  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100484544  E2F3; transcription factor E2F3 [KO:K06620]
100477654  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
100482871  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100470600  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100471095  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
100472241  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
100479738  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
100464732  POLK; DNA polymerase kappa isoform X2 [KO:K03511] [EC:]
100470703  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
100463584  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
100475861  TGFB3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
100475698  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:]
100482939  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:]
100479304  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100465063  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
100482997  MECOM; histone-lysine N-methyltransferase MECOM isoform X1 [KO:K04462] [EC:]
100484679  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
100484032  CTBP1; C-terminal-binding protein 1 isoform X2 [KO:K04496]
100470969  CTBP2; C-terminal-binding protein 2 isoform X1 [KO:K04496]
100477725  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:]
100478424  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)
aml04010  MAPK signaling pathway
aml04110  Cell cycle
aml04115  p53 signaling pathway
aml04151  PI3K-Akt signaling pathway
aml04210  Apoptosis
aml04350  TGF-beta signaling pathway
aml04640  Hematopoietic cell lineage
KO pathway

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