Abstract
The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph(+) ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Benzamides
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Cell Survival / drug effects
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Child
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DNA Methylation
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Gene Expression Regulation, Leukemic / genetics*
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Humans
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Imatinib Mesylate
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Kaplan-Meier Estimate
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Multicenter Studies as Topic / statistics & numerical data
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic
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Proportional Hazards Models
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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Radiation Chimera
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Randomized Controlled Trials as Topic / statistics & numerical data
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SOXC Transcription Factors / biosynthesis
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SOXC Transcription Factors / deficiency
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SOXC Transcription Factors / genetics
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SOXC Transcription Factors / physiology*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / drug effects
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Tumor Stem Cell Assay
Substances
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Benzamides
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Neoplasm Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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SOX4 protein, human
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SOXC Transcription Factors
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Sox4 protein, mouse
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Imatinib Mesylate