KEGG   PATHWAY: hsa05221
hsa05221                    Pathway                                
Acute myeloid leukemia - Homo sapiens (human)
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.
Human Diseases; Cancer: specific types
Pathway map
hsa05221  Acute myeloid leukemia

nt06210  ERK signaling
nt06214  PI3K signaling
nt06219  JAK-STAT signaling
nt06240  Transcription
nt06260  Colorectal cancer
nt06261  Gastric cancer
nt06262  Pancreatic cancer
nt06266  Non-small cell lung cancer
nt06268  Melanoma
nt06271  Endometrial cancer
nt06274  Thyroid cancer
nt06275  Acute myeloid leukemia
N00003  Mutation-activated KIT to RAS-ERK signaling pathway
N00004  Duplication or mutation-activated FLT3 to RAS-ERK signaling pathway
N00012  Mutation-activated KRAS/NRAS to ERK signaling pathway
N00031  Duplication or mutation-activated FLT3 to RAS-PI3K signaling pathway
N00032  Mutation-activated KRAS/NRAS to PI3K signaling pathway
N00046  Mutation-activated KIT to PI3K signaling pathway
N00054  Duplication or mutation-activated FLT3 to Jak-STAT signaling pathway
N00108  AML1-ETO fusion to transcriptional activtion
N00109  PML-RARA fusion to transcriptional activtion
N00110  PLZF-RARA fusion to transcriptional activtion
N00111  AML1-ETO fusion to CEBPA-mediated transcription
N00112  AML1-ETO fusion to PU.1-mediated transcription
N00113  PML-RARA fusion to transcriptional repression
N00114  PLZF-RARA fusion to transcriptional repression
N00116  Mutation-inactivated RUNX1 to transcription
H00003  Acute myeloid leukemia
D00094  Tretinoin (JAN/USP/INN)
D05029  Midostaurin (JAN/USAN/INN)
D10800  Gilteritinib fumarate (JAN/USAN)
Homo sapiens (human) [GN:hsa]
3815  KIT; KIT proto-oncogene, receptor tyrosine kinase [KO:K05091] [EC:]
2322  FLT3; fms related receptor tyrosine kinase 3 [KO:K05092] [EC:]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
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:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory 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:]
1978  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:]
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:]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
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:]
11040  PIM2; Pim-2 proto-oncogene, serine/threonine kinase [KO:K08806] [EC:]
861  RUNX1; RUNX family transcription factor 1 [KO:K08367]
1436  CSF1R; colony stimulating factor 1 receptor [KO:K05090] [EC:]
4353  MPO; myeloperoxidase [KO:K10789] [EC:]
1437  CSF2; colony stimulating factor 2 [KO:K05427]
3562  IL3; interleukin 3 [KO:K04736]
862  RUNX1T1; RUNX1 partner transcriptional co-repressor 1 [KO:K10053]
5371  PML; PML nuclear body scaffold [KO:K10054] [EC:2.3.2.-]
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 regulator 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 gamma receptor Ia [KO:K06498]
1053  CEBPE; CCAAT enhancer binding protein epsilon [KO:K10051]
597  BCL2A1; BCL2 related protein A1 [KO:K02162]
890  CCNA2; cyclin A2 [KO:K06627]
8900  CCNA1; cyclin A1 [KO:K06627]
4609  MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]
1848  DUSP6; dual specificity phosphatase 6 [KO:K21946] [EC:]
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]
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H.
The molecular pathogenesis of acute myeloid leukemia.
Crit Rev Oncol Hematol 56:195-221 (2005)
Tenen DG.
Disruption of differentiation in human cancer: AML shows the way.
Nat Rev Cancer 3:89-101 (2003)
Choudhary C, Muller-Tidow C, Berdel WE, Serve H.
Signal transduction of oncogenic Flt3.
Int J Hematol 82:93-9 (2005)
Stirewalt DL, Radich JP.
The role of FLT3 in haematopoietic malignancies.
Nat Rev Cancer 3:650-65 (2003)
Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, Cocco L.
Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.
Leukemia 20:911-28 (2006)
Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R.
Normal and oncogenic forms of the receptor tyrosine kinase kit.
Stem Cells 23:16-43 (2005)
Lorsbach RB, Downing JR.
The role of the AML1 transcription factor in leukemogenesis.
Int J Hematol 74:258-65 (2001)
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.
Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.
Blood 101:3164-73 (2003)
Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG.
ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression.
Blood 107:3330-8 (2006)
Roumier C, Fenaux P, Lafage M, Imbert M, Eclache V, Preudhomme C
New mechanisms of AML1 gene alteration in hematological malignancies.
Leukemia 17:9-16 (2003)
Scandura JM, Boccuni P, Cammenga J, Nimer SD
Transcription factor fusions in acute leukemia: variations on a theme.
Oncogene 21:3422-44 (2002)
Lutterbach B, Hiebert SW
Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation.
Gene 245:223-35 (2000)
Koschmieder S, Halmos B, Levantini E, Tenen DG
Dysregulation of the C/EBPalpha differentiation pathway in human cancer.
J Clin Oncol 27:619-28 (2009)
Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP
Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia.
Blood 106:2827-36 (2005)
Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG
Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
Blood 100:998-1007 (2002)
Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, Hiddemann W, Behre G
The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.
Blood 101:270-7 (2003)
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
Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells.
Mol Cell Biol 24:2890-904 (2004)
Muller C, Yang R, Park DJ, Serve H, Berdel WE, Koeffler HP
The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia.
Blood 96:3894-9 (2000)
Jing Y
The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia.
Leuk Lymphoma 45:639-48 (2004)
Alcalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, Sciurpi MT, Gelmetti V, Riganelli D, Minucci S, Fagioli M, Pelicci PG
Common themes in the pathogenesis of acute myeloid leukemia.
Oncogene 20:5680-94 (2001)
Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, Leiva M, Ablain J, Ambardekar C, McConnell MJ, Dick JE, Licht JD
Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC.
Blood 114:5499-511 (2009)
Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C.
The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia.
Leukemia 21:1638-47 (2007)
hsa04010  MAPK signaling pathway
hsa04110  Cell cycle
hsa04150  mTOR signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04210  Apoptosis
hsa04630  JAK-STAT signaling pathway
hsa04640  Hematopoietic cell lineage
KO pathway

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