title: Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex.
abstract: Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.
authors: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors: Michael
authors: M
authors: Heuser
authors: Haiyang
authors: H
authors: Yun
authors: Tobias
authors: T
authors: Berg
authors: Eric
authors: E
authors: Yung
authors: Bob
authors: B
authors: Argiropoulos
authors: Florian
authors: F
authors: Kuchenbauer
authors: Gyeongsin
authors: G
authors: Park
authors: Iyas
authors: I
authors: Hamwi
authors: Lars
authors: L
authors: Palmqvist
authors: Courteney K
authors: CK
authors: Lai
authors: Malina
authors: M
authors: Leung
authors: Grace
authors: G
authors: Lin
authors: Anuhar
authors: A
authors: Chaturvedi
authors: Basant Kumar
authors: BK
authors: Thakur
authors: Masayuki
authors: M
authors: Iwasaki
authors: Mikhail
authors: M
authors: Bilenky
authors: Nina
authors: N
authors: Thiessen
authors: Gordon
authors: G
authors: Robertson
authors: Martin
authors: M
authors: Hirst
authors: David
authors: D
authors: Kent
authors: Nicola K
authors: NK
authors: Wilson
authors: Bertie
authors: B
authors: Göttgens
authors: Connie
authors: C
authors: Eaves
authors: Michael L
authors: ML
authors: Cleary
authors: Marco
authors: M
authors: Marra
authors: Arnold
authors: A
authors: Ganser
authors: R Keith
authors: RK
authors: Humphries
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005799:Genes, Dominant / Q000235:genetics; D055014:Granulocyte-Macrophage Progenitor Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D046912:Multiprotein Complexes; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins