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Cancer Res. 2012 Apr 15;72(8):1929-34. doi: 10.1158/0008-5472.CAN-11-3589. Epub 2012 Feb 14.

The mixed lineage leukemia (MLL) fusion-associated gene AF4 promotes CD133 transcription.

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  • 1Donnelley Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada.

Abstract

The AC133 epitope has been used as a marker for both normal and cancer stem cells from multiple tissue lineages. To identify transcription factors that regulate CD133 expression, we conducted parallel large-scale RNA interference screens in Caco-2 cancer cells that endogenously express CD133 and in engineered HEK293 cells that express CD133 from a heterologous promoter. The transcription factor AF4 was identified following a comparative analysis between the two screens. We then showed that AF4 is a promoter of CD133 transcription in multiple cancer cell lines. Knockdown of AF4 resulted in a dramatic reduction in CD133 transcript levels. Importantly, a subset of pediatric acute lymphoblastic leukemias (ALL) harbor a fusion oncogene results from a chromosomal translocation that juxtaposes the mixed-lineage leukemia (MLL) gene and the AF4 gene. An investigation of the functional role of CD133 in the MLL-AF4-dependent ALL cells revealed that CD133 was required for leukemia cell survival. Together, our findings show AF4-dependent regulation of CD133 expression, which is required for the growth of ALL cells. CD133 may therefore represent a therapeutic target in a subset of cancers.

PMID:
22337994
[PubMed - indexed for MEDLINE]
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