KEGG   PATHWAY: map05221Help
Entry
map05221                    Pathway                                

Name
Acute myeloid leukemia
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; Cancers
BRITE hierarchy
Pathway map
Acute myeloid leukemia
map05221

All organismsOrtholog table
Disease
H00003  
Acute myeloid leukemia (AML)
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 : (2007)
DOI:10.1038/sj.leu.2404732
KO pathway
 

DBGET integrated database retrieval system