KEGG   PATHWAY: hsa05220Help
Entry
hsa05220                    Pathway                                

Name
Chronic myeloid leukemia - Homo sapiens (human)
Description
Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoetic cell lineages are involved in the process of clonal proliferation and differentiation. 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; Cancers
BRITE hierarchy
Pathway map
Chronic myeloid leukemia
hsa05220

All organismsOrtholog table
Disease
H00004  
Chronic myeloid leukemia (CML)
Drug
D01441  
Imatinib mesylate (USAN)
D03658  
Dasatinib (INN)
D06413  
Nilotinib hydrochloride hydrate (JAN)
D06414  
Dasatinib hydrate (JAN)
D08066  
Imatinib (INN)
D08953  
Nilotinib (USAN/INN)
D10202  
Bafetinib (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
613  
BCR; BCR, RhoGEF and GTPase activating protein [KO:K08878] [EC:2.7.11.1]
25  
ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2]
1398  
CRK; v-crk avian sarcoma virus CT10 oncogene homolog [KO:K04438]
1399  
CRKL; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
23624  
CBLC; Cbl proto-oncogene C [KO:K04707] [EC:2.3.2.27]
867  
CBL; Cbl proto-oncogene [KO:K04707] [EC:2.3.2.27]
868  
CBLB; Cbl proto-oncogene B [KO:K04707] [EC:2.3.2.27]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  
AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
572  
BAD; BCL2 associated agonist of cell death [KO:K02158]
598  
BCL2L1; BCL2 like 1 [KO:K04570]
1147  
CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
8517  
IKBKG; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma [KO:K07210]
4792  
NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  
NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  
RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
4193  
MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
7157  
TP53; tumor protein p53 [KO:K04451]
1027  
CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
2885  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
9846  
GAB2; GRB2 associated binding protein 2 [KO:K08091]
5781  
PTPN11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
6654  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
6464  
SHC1; SHC adaptor protein 1 [KO:K06279]
25759  
SHC2; SHC adaptor protein 2 [KO:K17447]
53358  
SHC3; SHC adaptor protein 3 [KO:K17448]
399694  
SHC4; SHC adaptor protein 4 [KO:K17449]
4609  
MYC; v-myc avian myelocytomatosis viral oncogene homolog [KO:K04377]
6776  
STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  
STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
1029  
CDKN2A; cyclin-dependent kinase inhibitor 2A [KO:K06621]
1026  
CDKN1A; cyclin-dependent kinase inhibitor 1A [KO:K06625]
595  
CCND1; cyclin D1 [KO:K04503]
1019  
CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
1021  
CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
5925  
RB1; retinoblastoma 1 [KO:K06618]
1869  
E2F1; E2F transcription factor 1 [KO:K17454]
1870  
E2F2; E2F transcription factor 2 [KO:K09389]
1871  
E2F3; E2F transcription factor 3 [KO:K06620]
7040  
TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  
TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  
TGFB3; transforming growth factor beta 3 [KO:K13377]
7046  
TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
7048  
TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
4089  
SMAD4; SMAD family member 4 [KO:K04501]
2122  
MECOM; MDS1 and EVI1 complex locus [KO:K04462]
861  
RUNX1; runt related transcription factor 1 [KO:K08367]
1487  
CTBP1; C-terminal binding protein 1 [KO:K04496]
1488  
CTBP2; C-terminal binding protein 2 [KO:K04496]
3065  
HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
3066  
HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
4088  
SMAD3; SMAD family member 3 [KO:K04500]
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)
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)
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)
Reference
  Authors
Mitani K.
  Title
Molecular mechanisms of leukemogenesis by AML1/EVI-1.
  Journal
Oncogene 23:4263-9 (2004)
Reference
  Authors
Dong M, Blobe GC.
  Title
Role of transforming growth factor-beta in hematologic malignancies.
  Journal
Blood 107:4589-96 (2006)
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)
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)
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)
KO pathway
 

DBGET integrated database retrieval system