Entry Name Chronic myeloid leukemia - Mus musculus (house mouse)
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 typesBRITE hierarchy
Pathway map Disease H00004 Chronic myeloid leukemia
Organism Mus musculus (house mouse) [GN:
mmu ]
Gene 107986 Ddb2; DNA damage-binding protein 2 isoform 1 [KO:K10140 ]
12015 Bad; bcl2-associated agonist of cell death isoform 1 [KO:K02158 ]
12018 Bak1; bcl-2 homologous antagonist/killer [KO:K14021 ]
12028 Bax; apoptosis regulator BAX isoform 1 [KO:K02159 ]
12048 Bcl2l1; bcl-2-like protein 1 isoform a [KO:K04570 ]
12394 Runx1; runt-related transcription factor 1 isoform 1 [KO:K08367 ]
12443 Ccnd1; G1/S-specific cyclin-D1 isoform 2 [KO:K04503 ]
12575 Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625 ]
12576 Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624 ]
12578 Cdkn2a; cyclin-dependent kinase inhibitor 2A isoform p19ARF [KO:K06621 ]
12675 Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform 2 [KO:K04467 ] [EC:2.7.11.10 ]
13197 Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402 ]
13555 E2f1; transcription factor E2F1 isoform a [KO:K17454 ]
13557 E2f3; transcription factor E2F3 isoform E2f3a [KO:K06620 ]
14389 Gab2; GRB2-associated-binding protein 2 isoform 2 [KO:K08091 ]
14784 Grb2; growth factor receptor-bound protein 2 [KO:K04364 ]
16150 Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1 [KO:K07209 ] [EC:2.7.11.10 ]
16151 Ikbkg; NF-kappa-B essential modulator isoform 1 [KO:K07210 ]
17127 Smad3; mothers against decapentaplegic homolog 3 [KO:K23605 ]
17128 Smad4; mothers against decapentaplegic homolog 4 isoform 1 [KO:K04501 ]
17869 Myc; myc proto-oncogene protein isoform a [KO:K04377 ]
17873 Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402 ]
18033 Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 1 [KO:K02580 ]
18706 Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
18707 Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform a [KO:K00922 ] [EC:2.7.1.153 ]
18708 Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 2 [KO:K02649 ]
18709 Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform 1 [KO:K02649 ]
18710 Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649 ]
19247 Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform b [KO:K07293 ] [EC:3.1.3.48 ]
19645 Rb1; retinoblastoma-associated protein [KO:K06618 ]
19697 Rela; transcription factor p65 isoform 1 [KO:K04735 ]
20416 Shc1; SHC-transforming protein 1 isoform a [KO:K06279 ]
20850 Stat5a; signal transducer and activator of transcription 5A isoform 1 [KO:K11223 ]
20851 Stat5b; signal transducer and activator of transcription 5B [KO:K11224 ]
21803 Tgfb1; transforming growth factor beta-1 proprotein preproprotein [KO:K13375 ]
21808 Tgfb2; transforming growth factor beta-2 proprotein isoform 1 preproprotein [KO:K13376 ]
21809 Tgfb3; transforming growth factor beta-3 proprotein precursor [KO:K13377 ]
22059 Trp53; cellular tumor antigen p53 isoform a [KO:K04451 ]
23882 Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402 ]
242705 E2f2; transcription factor E2F2 isoform 1 [KO:K09389 ]
26395 Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368 ] [EC:2.7.12.2 ]
26396 Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369 ] [EC:2.7.12.2 ]
74769 Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Ren R.
Title Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Journal 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 Reference Authors Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM.
Title The biology of chronic myeloid leukemia.
Journal Reference Authors Mitani K.
Title Molecular mechanisms of leukemogenesis by AML1/EVI-1.
Journal Reference Authors Dong M, Blobe GC.
Title Role of transforming growth factor-beta in hematologic malignancies.
Journal Reference 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 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 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 Related KO pathway
