KEGG   PATHWAY: chx05221
Entry
chx05221                    Pathway                                

Name
Acute myeloid leukemia - Capra hircus (goat)
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
chx05221  Acute myeloid leukemia
chx05221

Organism
Capra hircus (goat) [GN:chx]
Gene
100861386  KIT; KIT proto-oncogene receptor tyrosine kinase [KO:K05091] [EC:2.7.10.1]
102189319  FLT3; fms related tyrosine kinase 3 [KO:K05092] [EC:2.7.10.1]
102185042  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
102168391  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
102177551  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
102179343  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
102170135  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
102188710  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
100860904  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
102174051  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102187521  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
102181262  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
102177406  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102171591  IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
102175660  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
102174096  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
102189930  BAD; BCL2 associated agonist of cell death [KO:K02158]
100860902  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
100861234  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
100861297  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
102169319  ribosomal protein S6 kinase beta-1-like [KO:K04688] [EC:2.7.11.1]
102182675  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
102170356  GRB2; growth factor receptor bound protein 2 [KO:K04364]
102185660  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
102184154  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
102186668  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
102187180  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
102172519  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
102169370  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
102174360  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
108638619  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
102190520  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102175285  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102186040  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102188824  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102186154  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
102185866  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
102176415  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
102191659  PIM1; Pim-1 proto-oncogene, serine/threonine kinase [KO:K04702] [EC:2.7.11.1]
102170766  PIM2; Pim-2 proto-oncogene, serine/threonine kinase [KO:K08806] [EC:2.7.11.1]
102178020  RUNX1; runt related transcription factor 1 [KO:K08367]
100861303  CSF1R; colony stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]
102185772  MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
100861208  CSF2; colony stimulating factor 2 [KO:K05427]
102190507  IL3; interleukin-3 [KO:K04736]
102171993  RUNX1T1; RUNX1 translocation partner 1 [KO:K10053]
102173973  PML; promyelocytic leukemia [KO:K10054]
102188350  RARA; retinoic acid receptor alpha [KO:K08527]
102178465  ZBTB16; zinc finger and BTB domain containing 16 [KO:K10055]
102177713  CEBPA; CCAAT/enhancer binding protein alpha [KO:K09055]
102178971  PER2; period circadian clock 2 [KO:K02633]
102186416  SPI1; Spi-1 proto-oncogene [KO:K09438]
100861226  CD14; CD14 molecule [KO:K04391]
102177056  CD14; CD14 molecule [KO:K04391]
102180100  ITGAM; integrin subunit alpha M [KO:K06461]
102173987  high affinity immunoglobulin gamma Fc receptor I [KO:K06498]
102174211  CEBPE; CCAAT/enhancer binding protein epsilon [KO:K10051]
102172845  BCL2A1; BCL2 related protein A1 [KO:K02162]
102176051  CCNA1; cyclin A1 [KO:K06627]
102190390  CCNA2; cyclin A2 [KO:K06627]
102171262  MYC; v-myc avian myelocytomatosis viral oncogene homolog [KO:K04377]
102172327  DUSP6; dual specificity phosphatase 6 [KO:K21946] [EC:3.1.3.16 3.1.3.48]
102180076  JUP; junction plakoglobin [KO:K10056]
102173736  TCF7; transcription factor 7 (T-cell specific, HMG-box) [KO:K02620]
102187776  TCF7L1; transcription factor 7 like 1 [KO:K04490]
102180102  TCF7L2; transcription factor 7 like 2 [KO:K04491]
100860901  LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
102169650  CCND1; cyclin D1 [KO:K04503]
102174518  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
chx04010  MAPK signaling pathway
chx04110  Cell cycle
chx04150  mTOR signaling pathway
chx04151  PI3K-Akt signaling pathway
chx04210  Apoptosis
chx04630  JAK-STAT signaling pathway
chx04640  Hematopoietic cell lineage
KO pathway
ko05221   
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