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Cancer Cell. 2008 May;13(5):432-40. doi: 10.1016/j.ccr.2008.03.005.

Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.

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  • 1University of Minnesota Cancer Center, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455, USA.

Abstract

The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

PMID:
18455126
PMCID:
PMC2430522
DOI:
10.1016/j.ccr.2008.03.005
[PubMed - indexed for MEDLINE]
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