KEGG   PATHWAY: mpah05221
Entry
mpah05221                   Pathway                                

Name
Acute myeloid leukemia - Mus pahari (shrew mouse)
Description
Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
Class
Human Diseases; Cancer: specific types
Pathway map
mpah05221  Acute myeloid leukemia
mpah05221

Organism
Mus pahari (shrew mouse) [GN:mpah]
Gene
110330230  Kit; mast/stem cell growth factor receptor Kit isoform X1 [KO:K05091] [EC:2.7.10.1]
110312926  Flt3; receptor-type tyrosine-protein kinase FLT3 [KO:K05092] [EC:2.7.10.1]
110323448  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110319750  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110327251  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110328811  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110336420  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
110322865  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110317258  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110324386  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110322284  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110334538  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
110336182  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
110313464  Ikbkg; NF-kappa-B essential modulator isoform X1 [KO:K07210]
110319789  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
110317041  Rela; transcription factor p65 [KO:K04735]
110326250  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110323363  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
110336761  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
110315992  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
110331448  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
110331195  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
110335780  Sos1; son of sevenless homolog 1 [KO:K03099]
110324314  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
110318967  GTPase HRas-like isoform X1 [KO:K02833]
110319567  Hras; GTPase HRas [KO:K02833]
110338480  GTPase HRas-like [KO:K02833]
110333346  GTPase HRas-like [KO:K02833]
110320340  Nras; GTPase NRas [KO:K07828]
110316221  Kras; GTPase KRas isoform X1 [KO:K07827]
110314283  Araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
110316269  Braf; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
110314893  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110327244  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110326321  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
110329343  Mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
110320020  Mapk3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
110332765  Stat3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
110331871  LOW QUALITY PROTEIN: signal transducer and activator of transcription 5A-like [KO:K11223]
110331105  Stat5b; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
110338042  Pim1; serine/threonine-protein kinase pim-1 [KO:K04702] [EC:2.7.11.1]
110313719  Pim2; serine/threonine-protein kinase pim-2 [KO:K08806] [EC:2.7.11.1]
110329713  Runx1; runt-related transcription factor 1 isoform X1 [KO:K08367]
110333327  Csf1r; macrophage colony-stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]
110331385  Mpo; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
110332438  Csf2; granulocyte-macrophage colony-stimulating factor [KO:K05427]
110332758  LOW QUALITY PROTEIN: interleukin-3-like [KO:K04736]
110338627  Runx1t1; protein CBFA2T1 isoform X1 [KO:K10053]
110327943  Pml; protein PML [KO:K10054]
110331544  Rara; retinoic acid receptor alpha isoform X1 [KO:K08527]
110327725  Zbtb16; zinc finger and BTB domain-containing protein 16 isoform X1 [KO:K10055]
110324171  Cebpa; CCAAT/enhancer-binding protein alpha [KO:K09055]
110321613  Per2; period circadian protein homolog 2 isoform X1 [KO:K02633]
110318694  Spi1; transcription factor PU.1 isoform X1 [KO:K09438]
110333539  Cd14; monocyte differentiation antigen CD14 [KO:K04391]
110327528  Itgam; integrin alpha-M isoform X1 [KO:K06461]
110320097  high affinity immunoglobulin gamma Fc receptor I [KO:K06498]
110325926  Cebpe; CCAAT/enhancer-binding protein epsilon [KO:K10051]
110320587  Ccna1; cyclin-A1 [KO:K06627]
110320068  Ccna2; cyclin-A2 [KO:K06627]
110334656  Myc; myc proto-oncogene protein [KO:K04377]
110326343  Dusp6; dual specificity protein phosphatase 6 isoform X1 [KO:K21946] [EC:3.1.3.16 3.1.3.48]
110331174  Jup; junction plakoglobin [KO:K10056]
110332085  Tcf7; transcription factor 7 isoform X1 [KO:K02620]
110315696  Tcf7l1; transcription factor 7-like 1 isoform X1 [KO:K04490]
110313411  Tcf7l2; transcription factor 7-like 2 isoform X1 [KO:K04491]
110319903  Lef1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
110322378  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
110338015  Ppard; peroxisome proliferator-activated receptor delta isoform X1 [KO:K04504]
Compound
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H.
  Title
The molecular pathogenesis of acute myeloid leukemia.
  Journal
Crit Rev Oncol Hematol 56:195-221 (2005)
DOI:10.1016/j.critrevonc.2004.10.012
Reference
  Authors
Tenen DG.
  Title
Disruption of differentiation in human cancer: AML shows the way.
  Journal
Nat Rev Cancer 3:89-101 (2003)
DOI:10.1038/nrc989
Reference
  Authors
Choudhary C, Muller-Tidow C, Berdel WE, Serve H.
  Title
Signal transduction of oncogenic Flt3.
  Journal
Int J Hematol 82:93-9 (2005)
DOI:10.1532/IJH97.05090
Reference
  Authors
Stirewalt DL, Radich JP.
  Title
The role of FLT3 in haematopoietic malignancies.
  Journal
Nat Rev Cancer 3:650-65 (2003)
DOI:10.1038/nrc1169
Reference
  Authors
Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, Cocco L.
  Title
Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.
  Journal
Leukemia 20:911-28 (2006)
DOI:10.1038/sj.leu.2404245
Reference
  Authors
Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R.
  Title
Normal and oncogenic forms of the receptor tyrosine kinase kit.
  Journal
Stem Cells 23:16-43 (2005)
DOI:10.1634/stemcells.2004-0117
Reference
  Authors
Lorsbach RB, Downing JR.
  Title
The role of the AML1 transcription factor in leukemogenesis.
  Journal
Int J Hematol 74:258-65 (2001)
DOI:10.1007/BF02982058
Reference
  Authors
Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, Steffen B, Matsumura I, Kanakura Y, Bohmer FD, Muller-Tidow C, Berdel WE, Serve H.
  Title
Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.
  Journal
Blood 101:3164-73 (2003)
DOI:10.1182/blood-2002-06-1677
Reference
  Authors
Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG.
  Title
ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression.
  Journal
Blood 107:3330-8 (2006)
DOI:10.1182/blood-2005-07-3068
Reference
  Authors
Roumier C, Fenaux P, Lafage M, Imbert M, Eclache V, Preudhomme C
  Title
New mechanisms of AML1 gene alteration in hematological malignancies.
  Journal
Leukemia 17:9-16 (2003)
DOI:10.1038/sj.leu.2402766
Reference
  Authors
Scandura JM, Boccuni P, Cammenga J, Nimer SD
  Title
Transcription factor fusions in acute leukemia: variations on a theme.
  Journal
Oncogene 21:3422-44 (2002)
DOI:10.1038/sj.onc.1205315
Reference
  Authors
Lutterbach B, Hiebert SW
  Title
Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation.
  Journal
Gene 245:223-35 (2000)
DOI:10.1016/S0378-1119(00)00014-7
Reference
  Authors
Koschmieder S, Halmos B, Levantini E, Tenen DG
  Title
Dysregulation of the C/EBPalpha differentiation pathway in human cancer.
  Journal
J Clin Oncol 27:619-28 (2009)
DOI:10.1200/JCO.2008.17.9812
Reference
  Authors
Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP
  Title
Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia.
  Journal
Blood 106:2827-36 (2005)
DOI:10.1182/blood-2005-01-0358
Reference
  Authors
Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG
  Title
Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
  Journal
Blood 100:998-1007 (2002)
DOI:10.1182/blood.V100.3.998
Reference
  Authors
Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, Hiddemann W, Behre G
  Title
The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.
  Journal
Blood 101:270-7 (2003)
DOI:10.1182/blood-2002-04-1288
Reference
  Authors
Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Kohler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert SW, Koeffler HP, Berdel WE, Serve H
  Title
Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells.
  Journal
Mol Cell Biol 24:2890-904 (2004)
DOI:10.1128/MCB.24.7.2890-2904.2004
Reference
  Authors
Muller C, Yang R, Park DJ, Serve H, Berdel WE, Koeffler HP
  Title
The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia.
  Journal
Blood 96:3894-9 (2000)
Reference
  Authors
Jing Y
  Title
The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia.
  Journal
Leuk Lymphoma 45:639-48 (2004)
DOI:10.1080/10428190310001609933
Reference
  Authors
Alcalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, Sciurpi MT, Gelmetti V, Riganelli D, Minucci S, Fagioli M, Pelicci PG
  Title
Common themes in the pathogenesis of acute myeloid leukemia.
  Journal
Oncogene 20:5680-94 (2001)
DOI:10.1038/sj.onc.1204642
Reference
  Authors
Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, Leiva M, Ablain J, Ambardekar C, McConnell MJ, Dick JE, Licht JD
  Title
Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC.
  Journal
Blood 114:5499-511 (2009)
DOI:10.1182/blood-2009-03-206524
Reference
  Authors
Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C.
  Title
The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia.
  Journal
Leukemia 21:1638-47 (2007)
DOI:10.1038/sj.leu.2404732
Related
pathway
mpah04010  MAPK signaling pathway
mpah04110  Cell cycle
mpah04150  mTOR signaling pathway
mpah04151  PI3K-Akt signaling pathway
mpah04210  Apoptosis
mpah04630  JAK-STAT signaling pathway
mpah04640  Hematopoietic cell lineage
KO pathway
ko05221   
LinkDB

DBGET integrated database retrieval system