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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen
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Antigens, CD / biosynthesis
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Antigens, CD / genetics*
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Blotting, Western
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Caco-2 Cells
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Gene Expression Regulation, Neoplastic / genetics*
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Glycoproteins / biosynthesis
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Glycoproteins / genetics*
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Histone-Lysine N-Methyltransferase
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Humans
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Leukemia, Biphenotypic, Acute / genetics*
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Leukemia, Biphenotypic, Acute / metabolism
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Leukemia, Biphenotypic, Acute / pathology
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Neoplastic Stem Cells / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Peptides / genetics*
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RNA Interference
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Transcription, Genetic
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Transcriptional Elongation Factors
Substances
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AC133 Antigen
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Antigens, CD
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DNA-Binding Proteins
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Glycoproteins
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KMT2A protein, human
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Nuclear Proteins
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Oncogene Proteins, Fusion
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PROM1 protein, human
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Peptides
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Transcriptional Elongation Factors
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Myeloid-Lymphoid Leukemia Protein
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AFF1 protein, human
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Histone-Lysine N-Methyltransferase