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

Cancer Research
Anthony B MakJason Moffat

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.

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Citations

Jun 25, 2013·Briefings in Functional Genomics·Anthony B Mak, Jason Moffat
Mar 5, 2014·The American Journal of Pathology·Anthony B MakMei-Yu Hsu
Nov 6, 2014·Hematological Oncology·Aroonima MisraAnita Chopra
Feb 22, 2014·Journal of Molecular Biology·Anthony B MakJason Moffat
Jan 1, 2012·Cancers·Erica Ballabio, Thomas A Milne
Feb 2, 2018·Proceedings of the National Academy of Sciences of the United States of America·Yu-Ting TanYuet Wai Kan
Sep 24, 2020·Future Oncology·Athanasios Mavratzas, Frederik Marmé
Aug 19, 2017·Cellular and Molecular Life Sciences : CMLS·Camille Malouf, Katrin Ottersbach
Dec 12, 2020·International Journal of Molecular Sciences·Elzbieta PorebaJulia Durzynska

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