KEGG PATHWAY: hsa05220

PATHWAY: hsa05220

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

Pathway map

hsa05220

Chronic myeloid leukemia

Disease

H00004

Chronic myeloid leukemia (CML)

Drug

D01441	Imatinib mesilate (JAN)
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; breakpoint cluster region [KO:K08878] [EC:2.7.11.1]
25	ABL1; c-abl oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2]
1398	CRK; v-crk sarcoma virus CT10 oncogene homolog (avian) [KO:K04438]
1399	CRKL; v-crk sarcoma virus CT10 oncogene homolog (avian)-like [KO:K04438]
23624	CBLC; Cbl proto-oncogene, E3 ubiquitin protein ligase C [KO:K04707] [EC:6.3.2.19]
867	CBL; Cbl proto-oncogene, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
868	CBLB; Cbl proto-oncogene, E3 ubiquitin protein ligase B [KO:K04707] [EC:6.3.2.19]
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 (alpha) [KO:K02649]
23533	PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296	PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503	PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
207	AKT1; v-akt murine thymoma viral oncogene homolog 1 [KO:K04456] [EC:2.7.11.1]
208	AKT2; v-akt murine thymoma viral oncogene homolog 2 [KO:K04456] [EC:2.7.11.1]
10000	AKT3; v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma) [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; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha [KO:K04734]
4790	NFKB1; nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 [KO:K02580]
5970	RELA; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
4193	MDM2; MDM2 oncogene, E3 ubiquitin protein ligase [KO:K06643] [EC:6.3.2.19]
7157	TP53; tumor protein p53 [KO:K04451]
1027	CDKN1B; cyclin-dependent kinase inhibitor 1B (p27, Kip1) [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; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655	SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265	HRAS; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845	KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893	NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
5894	RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [KO:K04366] [EC:2.7.11.1]
369	ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
673	BRAF; v-raf murine sarcoma viral oncogene homolog B1 [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]
25759	SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K06279]
399694	SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K06279]
53358	SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K06279]
6464	SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
4609	MYC; v-myc myelocytomatosis viral oncogene homolog (avian) [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 (p21, Cip1) [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:K06620]
1871	E2F3; E2F transcription factor 3 [KO:K06620]
1870	E2F2; E2F transcription factor 2 [KO:K09389]
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 II (70/80kDa) [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

PMID:15719031

Authors

Ren R.

Title

Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.

Journal

Nat Rev Cancer 5:172-83 (2005)

Reference

PMID:11071626

Authors

Deininger MW, Goldman JM, Melo JV.

Title

The molecular biology of chronic myeloid leukemia.

Journal

Blood 96:3343-56 (2000)

Reference

PMID:14982876

Authors

Calabretta B, Perrotti D.

Title

The biology of CML blast crisis.

Journal

Blood 103:4010-22 (2004)

Reference

PMID:10403855

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

PMID:15156182

Authors

Mitani K.

Title

Molecular mechanisms of leukemogenesis by AML1/EVI-1.

Journal

Oncogene 23:4263-9 (2004)

Reference

PMID:16484590

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

PMID:12801837

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

PMID:11160144

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

PMID:12244301

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)

KO pathway

ko05220

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Ontology (3)   
   KEGG BRITE (3)   
Pathway (1)   
   BioSystems (1)   
Disease (1)   
   KEGG DISEASE (1)   
Drug (7)   
   KEGG DRUG (7)   
Genome (1)   
   KEGG GENOME (1)   
Gene (73)   
   KEGG GENES (73)   
All databases (86)   

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