KEGG   PATHWAY: cge05220
Entry
cge05220                    Pathway                                

Name
Chronic myeloid leukemia - Cricetulus griseus (Chinese hamster)
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
cge05220  Chronic myeloid leukemia
cge05220

Organism
Cricetulus griseus (Chinese hamster) [GN:cge]
Gene
100768252  Bcr; breakpoint cluster region protein isoform X2 [KO:K08878] [EC:2.7.11.1]
100768098  Abl1; tyrosine-protein kinase ABL1 isoform X2 [KO:K06619] [EC:2.7.10.2]
100752014  Crkl; crk-like protein isoform X1 [KO:K04438]
100762827  Crk; adapter molecule crk isoform X2 [KO:K04438]
100754737  Cbl; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
100689251  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100769225  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100689252  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100771181  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
100750761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100774067  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100768351  Akt2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100752454  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100769460  Akt1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100760426  Bad; bcl2-associated agonist of cell death isoform X2 [KO:K02158]
100689371  Bcl2l1; bcl-2-like protein 1 [KO:K04570]
100754432  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X5 [KO:K04467] [EC:2.7.11.10]
100750488  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100759762  Ikbkg; NF-kappa-B essential modulator isoform X6 [KO:K07210]
100754153  Nfkbia; NF-kappa-B inhibitor alpha isoform X2 [KO:K04734]
100770607  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580]
100763542  Rela; transcription factor p65 isoform X4 [KO:K04735]
100770120  Mdm2; E3 ubiquitin-protein ligase Mdm2 isoform X3 [KO:K06643] [EC:2.3.2.27]
100682525  Tp53; cellular tumor antigen p53 [KO:K04451]
100689401  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100769627  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100771626  Gab2; GRB2-associated-binding protein 2 isoform X3 [KO:K08091]
100771077  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform X2 [KO:K07293] [EC:3.1.3.48]
100757521  Sos1; son of sevenless homolog 1 isoform X2 [KO:K03099]
100769325  Sos2; son of sevenless homolog 2 isoform X3 [KO:K03099]
100773737  Hras; GTPase HRas isoform X2 [KO:K02833]
100763178  Kras; GTPase KRas isoform X4 [KO:K07827]
113839127  GTPase KRas-like [KO:K07827]
113837935  GTPase KRas-like isoform X2 [KO:K07827]
113837956  GTPase KRas-like [KO:K07827]
113838653  GTPase KRas-like isoform X2 [KO:K07827]
113838692  GTPase KRas-like [KO:K07827]
113838722  GTPase KRas-like isoform X1 [KO:K07827]
113838818  GTPase KRas-like [KO:K07827]
113837633  GTPase KRas-like isoform X1 [KO:K07827]
113838146  GTPase KRas-like isoform X1 [KO:K07827]
113838876  GTPase KRas-like [KO:K07827]
113838228  GTPase KRas-like isoform X1 [KO:K07827]
113839011  GTPase KRas-like [KO:K07827]
100771078  GTPase KRas-like isoform X2 [KO:K07827]
113837960  GTPase KRas-like [KO:K07827]
113838098  GTPase KRas-like [KO:K07827]
113838326  GTPase KRas-like [KO:K07827]
113838417  GTPase KRas-like isoform X1 [KO:K07827]
113838488  GTPase KRas-like [KO:K07827]
113838583  GTPase KRas-like isoform X1 [KO:K07827]
113838676  GTPase KRas-like [KO:K07827]
113838679  GTPase KRas-like isoform X1 [KO:K07827]
113838746  GTPase KRas-like [KO:K07827]
113838796  GTPase KRas-like isoform X1 [KO:K07827]
113838871  GTPase KRas-like [KO:K07827]
113838872  GTPase KRas-like [KO:K07827]
113838892  GTPase KRas-like [KO:K07827]
113838898  GTPase KRas-like [KO:K07827]
113838914  GTPase KRas-like [KO:K07827]
113838921  GTPase KRas-like [KO:K07827]
113838942  GTPase KRas-like isoform X1 [KO:K07827]
113838943  GTPase KRas-like isoform X1 [KO:K07827]
113839007  GTPase HRas-like isoform X1 [KO:K07827]
118239746  GTPase KRas-like isoform X1 [KO:K07827]
118239767  GTPase KRas-like isoform X1 [KO:K07827]
118239768  GTPase KRas-like [KO:K07827]
118239770  GTPase KRas-like [KO:K07827]
118239801  GTPase KRas-like [KO:K07827]
118239825  GTPase KRas-like isoform X1 [KO:K07827]
100757614  Nras; GTPase NRas [KO:K07828]
100769018  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
100751432  Araf; serine/threonine-protein kinase A-Raf isoform X5 [KO:K08845] [EC:2.7.11.1]
100771486  Braf; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:2.7.11.1]
100689403  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
113835540  dual specificity mitogen-activated protein kinase kinase 1-like isoform X1 [KO:K04368] [EC:2.7.12.2]
103158537  dual specificity mitogen-activated protein kinase kinase 1-like isoform X2 [KO:K04368] [EC:2.7.12.2]
100774204  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X2 [KO:K04369] [EC:2.7.12.2]
100759514  Mapk1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100753149  Mapk3; mitogen-activated protein kinase 3 isoform X2 [KO:K04371] [EC:2.7.11.24]
100758936  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
100761269  Shc2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
100760879  Shc3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100763505  Shc4; SHC-transforming protein 4 isoform X2 [KO:K17449]
100773301  Myc; myc proto-oncogene protein isoform X2 [KO:K04377]
100755571  signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
100750571  signal transducer and activator of transcription 5B isoform X2 [KO:K11224]
100764983  tumor suppressor ARF isoform X2 [KO:K06621]
103160601  Cdkn1a; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
100689063  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
100760122  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100764515  Cdk6; cyclin-dependent kinase 6 isoform X2 [KO:K02091] [EC:2.7.11.22]
100752928  Rb1; LOW QUALITY PROTEIN: retinoblastoma-associated protein isoform X2 [KO:K06618]
100758556  E2f1; LOW QUALITY PROTEIN: transcription factor E2F1 isoform X2 [KO:K17454]
100754522  E2f2; transcription factor E2F2 isoform X2 [KO:K09389]
100754647  E2f3; transcription factor E2F3 isoform X1 [KO:K06620]
103159266  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X2 [KO:K04402]
100759228  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100766127  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100689032  Bax; apoptosis regulator BAX [KO:K02159]
100689368  Bak1; bcl-2 homologous antagonist/killer [KO:K14021]
100756705  Ddb2; LOW QUALITY PROTEIN: DNA damage-binding protein 2 [KO:K10140]
100758099  Polk; DNA polymerase kappa isoform X3 [KO:K03511] [EC:2.7.7.7]
100773359  Tgfb1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
100774918  Tgfb2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
100756831  Tgfb3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
100772727  Tgfbr1; TGF-beta receptor type-1 isoform X3 [KO:K04674] [EC:2.7.11.30]
100773953  Tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100759220  Smad3; mothers against decapentaplegic homolog 3 isoform X3 [KO:K23605]
100770737  Smad4; mothers against decapentaplegic homolog 4 isoform X2 [KO:K04501]
100768628  Mecom; histone-lysine N-methyltransferase MECOM isoform X1 [KO:K04462] [EC:2.1.1.367]
100758283  Runx1; runt-related transcription factor 1 isoform X5 [KO:K08367]
100769412  Ctbp2; C-terminal-binding protein 2 isoform X1 [KO:K04496]
100766703  Ctbp1; C-terminal-binding protein 1 isoform X4 [KO:K04496]
100762805  LOW QUALITY PROTEIN: C-terminal-binding protein 2-like [KO:K04496]
100764557  Hdac2; histone deacetylase 2 isoform X2 [KO:K06067] [EC:3.5.1.98]
100752721  Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
100761556  histone deacetylase 1-like [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
cge04010  MAPK signaling pathway
cge04110  Cell cycle
cge04115  p53 signaling pathway
cge04151  PI3K-Akt signaling pathway
cge04210  Apoptosis
cge04350  TGF-beta signaling pathway
cge04640  Hematopoietic cell lineage
KO pathway
ko05220   
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