Entry Name Acute myeloid leukemia - Macaca mulatta (rhesus monkey)
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 typesBRITE hierarchy
Pathway map Disease Organism Macaca mulatta (rhesus monkey) [GN:
mcc ]
Gene 574128 STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692 ]
574129 STAT5A; signal transducer and activator of transcription 5A isoform 2 [KO:K11223 ]
574371 CSF2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427 ]
694560 TCF7L1; transcription factor 7-like 1 isoform X2 [KO:K04490 ]
695064 ZBTB16; zinc finger and BTB domain-containing protein 16 [KO:K10055 ]
695776 LEF1; lymphoid enhancer-binding factor 1 isoform X3 [KO:K04492 ]
696476 PER2; period circadian protein homolog 2 isoform X2 [KO:K02633 ]
696749 RUNX1; runt-related transcription factor 1 [KO:K08367 ]
697482 CD14; monocyte differentiation antigen CD14 precursor [KO:K04391 ]
698996 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649 ]
700206 RARA; retinoic acid receptor alpha isoform X2 [KO:K08527 ]
701237 IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210 ]
701759 TCF7L2; transcription factor 7-like 2 isoform X9 [KO:K04491 ]
702041 GRB2; growth factor receptor-bound protein 2 [KO:K04364 ]
703628 EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
707310 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
709511 CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X3 [KO:K04467 ] [EC:2.7.11.10 ]
709760 STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224 ]
709959 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
710324 NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580 ]
710552 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
712010 SPI1; transcription factor PU.1 isoform X3 [KO:K09438 ]
713442 CEBPE; CCAAT/enhancer-binding protein epsilon [KO:K10051 ]
713777 SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099 ]
714664 FCGR1A; high affinity immunoglobulin gamma Fc receptor I precursor [KO:K06498 ]
715919 RELA; transcription factor p65 isoform X1 [KO:K04735 ]
716098 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
717153 CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055 ]
717740 BAD; bcl2-associated agonist of cell death [KO:K02158 ]
718861 PPARD; peroxisome proliferator-activated receptor delta isoform X1 [KO:K04504 ]
719367 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
721712 FLT3; LOW QUALITY PROTEIN: receptor-type tyrosine-protein kinase FLT3 [KO:K05092 ] [EC:2.7.10.1 ]
721821 MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369 ] [EC:2.7.12.2 ]
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 Reference Authors Tenen DG.
Title Disruption of differentiation in human cancer: AML shows the way.
Journal Reference Authors Choudhary C, Muller-Tidow C, Berdel WE, Serve H.
Title Signal transduction of oncogenic Flt3.
Journal Reference Authors Stirewalt DL, Radich JP.
Title The role of FLT3 in haematopoietic malignancies.
Journal 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 Reference Authors Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R.
Title Normal and oncogenic forms of the receptor tyrosine kinase kit.
Journal Reference Authors Lorsbach RB, Downing JR.
Title The role of the AML1 transcription factor in leukemogenesis.
Journal 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 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 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 Reference Authors Scandura JM, Boccuni P, Cammenga J, Nimer SD
Title Transcription factor fusions in acute leukemia: variations on a theme.
Journal Reference Authors Lutterbach B, Hiebert SW
Title Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation.
Journal Reference Authors Koschmieder S, Halmos B, Levantini E, Tenen DG
Title Dysregulation of the C/EBPalpha differentiation pathway in human cancer.
Journal 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 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 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 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 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 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 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 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 Related KO pathway
