title: An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model.
abstract: Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll-AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes.
authors.affiliation: Department of Genetics, Cell Biology and Development, Masonic Cancer Center, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Bergerson
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.forename: Raha A
authors.initials: RA
authors.lastname: Been
authors.forename: Sanne
authors.initials: S
authors.lastname: Lugthart
authors.forename: Miechaleen D
authors.initials: MD
authors.lastname: Diers
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Nixon
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.forename: Danhua
authors.initials: D
authors.lastname: Fan
authors.forename: Anne-Francoise J
authors.initials: AF
authors.lastname: Lamblin
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: John H
authors.initials: JH
authors.lastname: Kersey
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis / Q000379:methods; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional / Q000502:physiology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D020298:U937 Cells
chemical_list: C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein