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
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 School of Biological Sciences > 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: | https://repository.cshl.edu/id/eprint/26901 |
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