KEGG   PATHWAY: tmu05221
Entry
tmu05221                    Pathway                                

Name
Acute myeloid leukemia - Trichechus manatus latirostris (Florida manatee)
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
tmu05221  Acute myeloid leukemia
tmu05221

Organism
Trichechus manatus latirostris (Florida manatee) [GN:tmu]
Gene
101357486  mast/stem cell growth factor receptor Kit [KO:K05091] [EC:2.7.10.1]
101352048  receptor-type tyrosine-protein kinase FLT3 isoform X2 [KO:K05092] [EC:2.7.10.1]
101358678  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101346849  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101359658  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
101351035  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
101343804  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101347746  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101360493  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101356099  RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101350197  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101341290  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
101351256  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101347574  NF-kappa-B essential modulator isoform X1 [KO:K07210]
101351866  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101361706  transcription factor p65 [KO:K04735]
101352047  bcl2-associated agonist of cell death [KO:K02158]
101343808  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101361891  eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101343535  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
101354510  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101359012  growth factor receptor-bound protein 2 [KO:K04364]
101359592  son of sevenless homolog 1 isoform X1 [KO:K03099]
101347392  son of sevenless homolog 2 isoform X1 [KO:K03099]
101342804  GTPase HRas isoform X2 [KO:K02833]
101344230  GTPase NRas isoform X1 [KO:K07828]
101347525  GTPase KRas isoform X3 [KO:K07827]
101351589  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101353421  serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
101357840  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101343332  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101341078  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101340589  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101358526  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101342651  signal transducer and activator of transcription 3 isoform X3 [KO:K04692]
101343407  signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
101354148  signal transducer and activator of transcription 5B [KO:K11224]
101343784  serine/threonine-protein kinase pim-1 isoform X2 [KO:K04702] [EC:2.7.11.1]
101345626  serine/threonine-protein kinase pim-2 isoform X1 [KO:K08806] [EC:2.7.11.1]
101357079  runt-related transcription factor 1 [KO:K08367]
101360266  macrophage colony-stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]
101340378  myeloperoxidase [KO:K10789] [EC:1.11.2.2]
101357995  granulocyte-macrophage colony-stimulating factor [KO:K05427]
101344188  LOW QUALITY PROTEIN: protein CBFA2T1 [KO:K10053]
101356208  protein PML isoform X1 [KO:K10054]
101340976  retinoic acid receptor alpha isoform X3 [KO:K08527]
101350829  zinc finger and BTB domain-containing protein 16 [KO:K10055]
101344839  CCAAT/enhancer-binding protein alpha [KO:K09055]
101346172  period circadian protein homolog 2 [KO:K02633]
101352574  transcription factor PU.1 isoform X2 [KO:K09438]
101344479  LOW QUALITY PROTEIN: monocyte differentiation antigen CD14 [KO:K04391]
101344727  monocyte differentiation antigen CD14 [KO:K04391]
101357920  integrin alpha-M isoform X2 [KO:K06461]
101342556  LOW QUALITY PROTEIN: high affinity immunoglobulin gamma Fc receptor I [KO:K06498]
101343059  CCAAT/enhancer-binding protein epsilon [KO:K10051]
101360563  bcl-2-related protein A1 [KO:K02162]
101341432  cyclin-A2 [KO:K06627]
101347141  cyclin-A1 [KO:K06627]
101349786  myc proto-oncogene protein [KO:K04377]
101344321  dual specificity protein phosphatase 6 isoform X1 [KO:K21946] [EC:3.1.3.16 3.1.3.48]
101355667  junction plakoglobin [KO:K10056]
101350837  LOW QUALITY PROTEIN: transcription factor 7 [KO:K02620]
101341696  transcription factor 7-like 1 [KO:K04490]
101345532  transcription factor 7-like 2 isoform X1 [KO:K04491]
101345125  lymphoid enhancer-binding factor 1 isoform X2 [KO:K04492]
101359745  G1/S-specific cyclin-D1 [KO:K04503]
101360550  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
tmu04010  MAPK signaling pathway
tmu04110  Cell cycle
tmu04150  mTOR signaling pathway
tmu04151  PI3K-Akt signaling pathway
tmu04210  Apoptosis
tmu04630  JAK-STAT signaling pathway
tmu04640  Hematopoietic cell lineage
KO pathway
ko05221   
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