KEGG   PATHWAY: hsa05221Help
Entry
hsa05221                    Pathway                                

Name
Acute myeloid leukemia - Homo sapiens (human)
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
hsa05221

All organismsOrtholog table
Disease
H00003  
Acute myeloid leukemia (AML)
Drug
D10709  
Gilteritinib (USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3815  
KIT; KIT proto-oncogene receptor tyrosine kinase [KO:K05091] [EC:2.7.10.1]
2322  
FLT3; fms related tyrosine kinase 3 [KO:K05092] [EC:2.7.10.1]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  
AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
1147  
CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  
IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  
IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
4790  
NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  
RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
572  
BAD; BCL2 associated agonist of cell death [KO:K02158]
2475  
MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
1978  
EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
6198  
RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  
RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
2885  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  
HRAS; HRas proto-oncogene, GTPase [KO:K02833]
4893  
NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
6774  
STAT3; signal transducer and activator of transcription 3 [KO:K04692]
6776  
STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  
STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
5292  
PIM1; Pim-1 proto-oncogene, serine/threonine kinase [KO:K04702] [EC:2.7.11.1]
11040  
PIM2; Pim-2 proto-oncogene, serine/threonine kinase [KO:K08806] [EC:2.7.11.1]
861  
RUNX1; runt related transcription factor 1 [KO:K08367]
1436  
CSF1R; colony stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]
4353  
MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
1437  
CSF2; colony stimulating factor 2 [KO:K05427]
3562  
IL3; interleukin 3 [KO:K04736]
862  
RUNX1T1; RUNX1 translocation partner 1 [KO:K10053]
5371  
PML; promyelocytic leukemia [KO:K10054]
5914  
RARA; retinoic acid receptor alpha [KO:K08527]
7704  
ZBTB16; zinc finger and BTB domain containing 16 [KO:K10055]
1050  
CEBPA; CCAAT/enhancer binding protein alpha [KO:K09055]
8864  
PER2; period circadian clock 2 [KO:K02633]
6688  
SPI1; Spi-1 proto-oncogene [KO:K09438]
929  
CD14; CD14 molecule [KO:K04391]
3684  
ITGAM; integrin subunit alpha M [KO:K06461]
2209  
FCGR1A; Fc fragment of IgG receptor Ia [KO:K06498]
1053  
CEBPE; CCAAT/enhancer binding protein epsilon [KO:K10051]
597  
BCL2A1; BCL2 related protein A1 [KO:K02162]
4609  
MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]
1848  
DUSP6; dual specificity phosphatase 6 [KO:K21946] [EC:3.1.3.48 3.1.3.16]
3728  
JUP; junction plakoglobin [KO:K10056]
6932  
TCF7; transcription factor 7 [KO:K02620]
83439  
TCF7L1; transcription factor 7 like 1 [KO:K04490]
6934  
TCF7L2; transcription factor 7 like 2 [KO:K04491]
51176  
LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
595  
CCND1; cyclin D1 [KO:K04503]
5467  
PPARD; peroxisome proliferator activated receptor delta [KO:K04504]
8900  
CCNA1; cyclin A1 [KO:K06627]
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 : (2007)
DOI:10.1038/sj.leu.2404732
KO pathway
 

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