4299

AFF1

AF4|MLLT2|PBM1;AF4/FMR2 family, member 1;AFF1;AF4/FMR2 family, member 1

AF4/FMR2 family member 1|ALL1-fused gene from chromosome 4 protein|myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 2|pre-B-cell monocytic leukemia partner 1|protein AF-4|proto-oncogene AF4

4q21

protein-coding

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.