Entry
Name
Acute myeloid leukemia - Bos taurus (cow)
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
BRITE hierarchy
Pathway map
Ortholog table
Organism
Bos taurus (cow) [GN:
bta ]
Gene
282306 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
517948 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
504531 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
282308 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
286865 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
282307 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649 ]
616115 NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580 ]
615013 BAD; bcl2-associated agonist of cell death [KO:K02158 ]
509613 EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
535298 GRB2; growth factor receptor-bound protein 2 [KO:K04364 ]
537682 SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099 ]
101905399 LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368 ] [EC:2.7.12.2 ]
508541 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
282375 STAT5A; signal transducer and activator of transcription 5A [KO:K11223 ]
282376 STAT5B; signal transducer and activator of transcription 5B [KO:K11224 ]
529631 RUNX1; runt-related transcription factor 1 [KO:K08367 ]
281095 CSF2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427 ]
534401 ZBTB16; zinc finger and BTB domain-containing protein 16 [KO:K10055 ]
281677 CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055 ]
281048 CD14; monocyte differentiation antigen CD14 precursor [KO:K04391 ]
282227 FCGR1A; high affinity immunoglobulin gamma Fc receptor I precursor [KO:K06498 ]
534346 CEBPE; CCAAT/enhancer-binding protein epsilon [KO:K10051 ]
515303 TCF7L1; transcription factor 7-like 1 isoform X1 [KO:K04490 ]
353106 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
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 pathway
KO pathway