title: Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11.
abstract: Recurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFbeta-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBF beta-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBF beta-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbF beta-SMMHC.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation St, LRB/622, Worcester, MA 01605, USA.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Landrette
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
authors.forename: Karen
authors.initials: K
authors.lastname: Hensen
authors.forename: Sahar
authors.initials: S
authors.lastname: Barjesteh van Waalwijk van Doorn-Khosrovani
authors.forename: Paola N
authors.initials: PN
authors.lastname: Perrat
authors.forename: Wim J M
authors.initials: WJ
authors.lastname: Van de Ven
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Castilla
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D016196:S Phase / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C095514:CBFbeta-MYH11 fusion protein; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; C104382:PLAG1 protein, human; C114598:PLAGL2 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors