An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model

Bergerson, R. J., Collier, L. S., Sarver, A. L., Been, R. A., Lugthart, S., Diers, M. D., Zuber, J., Rappaport, A. R., Nixon, M. J., Silverstein, K. A. T., Fan, D. H., Lamblin, A. F. J., Wolff, L., Kersey, J. H., Delwel, R., Lowe, S. W., O'Sullivan, M. G., Kogan, S. C., Adams, D. J., Largaespada, D. A. (May 2012) An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. Blood, 119 (19). pp. 4512-4523. ISSN 0006-4971

URL: http://www.ncbi.nlm.nih.gov/pubmed/22427200
DOI: 10.1182/blood-2010-04-281428

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. (Blood. 2012; 119(19): 4512-4523)

Item Type: Paper
Uncontrolled Keywords: acute myeloid-leukemia fusion gene mice cancer expression locus mll aml overexpression translocations
Subjects: diseases & disorders > cancer
diseases & disorders
organism description > animal > mammal
organism description > model organism
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL labs > Lowe lab
Watson School > Publications
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 10 May 2012
Date Deposited: 31 Jan 2013 21:25
Last Modified: 13 Oct 2015 19:29
PMCID: PMC3362364
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26901

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