title: The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.
abstract: The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes.
authors.affiliation: Institut de recherches cliniques de Montréal, Montreal, QC, Canada.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khandanpour
authors.forename: Joseph
authors.initials: J
authors.lastname: Krongold
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.forename: Frederique
authors.initials: F
authors.lastname: Bouwman
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaudreau
authors.forename: Riyan
authors.initials: R
authors.lastname: Chen
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.forename: Evangelia
authors.initials: E
authors.lastname: Diamanti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hannah
authors.forename: Sara E
authors.initials: SE
authors.lastname: Meyer
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Bert A
authors.initials: BA
authors.lastname: van der Reijden
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.forename: Chandrashekhar V
authors.initials: CV
authors.lastname: Patel
authors.forename: Justine K
authors.initials: JK
authors.lastname: Peeters
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Bertie
authors.initials: B
authors.lastname: Göttgens
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006410:Hematopoiesis / Q000235:genetics; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C079873:Gfi1 protein, mouse; D006657:Histones; D018398:Homeodomain Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D016283:Proto-Oncogene Proteins p21(ras)