KEGG   PATHWAY: ssc05221
Entry
ssc05221                    Pathway                                

Name
Acute myeloid leukemia - Sus scrofa (pig)
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
ssc05221  Acute myeloid leukemia
ssc05221

Organism
Sus scrofa (pig) [GN:ssc]
Gene
396810  KIT; mast/stem cell growth factor receptor Kit precursor [KO:K05091] [EC:2.7.10.1]
100515445  FLT3; receptor-type tyrosine-protein kinase FLT3 isoform X2 [KO:K05092] [EC:2.7.10.1]
100518131  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100621789  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100622559  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100511937  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100739510  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100623707  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
100126861  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100513811  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100127478  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100135662  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
100101471  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100127355  IKBKG; NF-kappa-B essential modulator [KO:K07210]
751869  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
100135665  RELA; transcription factor p65 [KO:K04735]
100521065  BAD; LOW QUALITY PROTEIN: bcl2-associated agonist of cell death [KO:K02158]
100127359  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100627508  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100127158  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100512153  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100192436  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100156602  SOS2; son of sevenless homolog 2 [KO:K03099]
100520187  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
110259208  HRAS; GTPase HRas isoform X1 [KO:K02833]
100739349  NRAS; GTPase NRas precursor [KO:K07828]
100518251  KRAS; GTPase KRas isoform X2 [KO:K07827]
397601  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100514612  BRAF; serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:2.7.11.1]
100737448  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100233191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100525505  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100153927  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
445013  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
733648  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
397550  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
397340  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
100157844  PIM1; serine/threonine-protein kinase pim-1 [KO:K04702] [EC:2.7.11.1]
100621339  PIM2; serine/threonine-protein kinase pim-2 [KO:K08806] [EC:2.7.11.1]
100512633  RUNX1; runt-related transcription factor 1 [KO:K08367]
100517086  CSF1R; macrophage colony-stimulating factor 1 receptor isoform X1 [KO:K05090] [EC:2.7.10.1]
100517120  MPO; LOW QUALITY PROTEIN: myeloperoxidase [KO:K10789] [EC:1.11.2.2]
397208  CSF2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427]
100155449  RUNX1T1; LOW QUALITY PROTEIN: protein CBFA2T1 [KO:K10053]
100157336  PML; LOW QUALITY PROTEIN: protein PML [KO:K10054]
396709  RARA; retinoic acid receptor alpha isoform X2 [KO:K08527]
100625290  ZBTB16; zinc finger and BTB domain-containing protein 16 [KO:K10055]
397307  CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055]
100154609  PER2; period circadian protein homolog 2 isoform X1 [KO:K02633]
414912  SPI1; transcription factor PU.1 [KO:K09438]
100037938  CD14; monocyte differentiation antigen CD14 precursor [KO:K04391]
397459  ITGAM; integrin alpha-M isoform X2 [KO:K06461]
613130  FCGR1A; high affinity immunoglobulin gamma Fc receptor I precursor [KO:K06498]
100157564  CEBPE; CCAAT/enhancer-binding protein epsilon [KO:K10051]
100156860  BCL2A1; bcl-2-related protein A1 [KO:K02162]
100415929  CCNA2; cyclin-A2 [KO:K06627]
100156017  CCNA1; cyclin-A1 [KO:K06627]
448810  MYC; myc proto-oncogene protein [KO:K04377]
100622968  DUSP6; dual specificity protein phosphatase 6 [KO:K21946] [EC:3.1.3.16 3.1.3.48]
397592  JUP; junction plakoglobin [KO:K10056]
100512951  TCF7; transcription factor 7 isoform X1 [KO:K02620]
100523899  TCF7L1; LOW QUALITY PROTEIN: transcription factor 7-like 1 [KO:K04490]
100153922  TCF7L2; transcription factor 7-like 2 isoform X26 [KO:K04491]
100170126  LEF1; lymphoid enhancer-binding factor 1 [KO:K04492]
100738589  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
397297  PPARD; peroxisome proliferator-activated receptor delta [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
ssc04010  MAPK signaling pathway
ssc04110  Cell cycle
ssc04150  mTOR signaling pathway
ssc04151  PI3K-Akt signaling pathway
ssc04210  Apoptosis
ssc04630  JAK-STAT signaling pathway
ssc04640  Hematopoietic cell lineage
KO pathway
ko05221   
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