Abstract
We investigated the therapeutic potential of JQ1, an inhibitor of the BET class of human bromodomain proteins, in B-cell acute lymphoblastic leukemia (B-ALL). We show that JQ1 potently reduces the viability of B-ALL cell lines with high-risk cytogenetics. Among the most sensitive were lines with rearrangements of CRLF2, which is overexpressed in ~ 10% of B-ALL. CRLF2 heterodimerizes with the IL7 receptor (IL7R) and signals through JAK2, JAK1, and STAT5 to drive proliferation and suppress apoptosis. As previously observed, JQ1 induced the down-regulation of MYC transcription, the loss of BRD4 at the MYC promoter, and the reduced expression of c-Myc target genes. Strikingly, JQ1 also down-regulated IL7R transcription, depleted BRD4 from the IL7R promoter, and reduced JAK2 and STAT5 phosphorylation. Genome-wide expression profiling demonstrated a restricted effect of JQ1 on transcription, with MYC and IL7R being among the most down-regulated genes. Indeed, IL7R was the only cytokine receptor in CRLF2-rearranged B-ALL cells significantly down-regulated by JQ1 treatment. In mice xenografted with primary human CRLF2-rearranged B-ALL, JQ1 suppressed c-Myc expression and STAT5 phosphorylation and significantly prolonged survival. Thus, bromodomain inhibition is a promising therapeutic strategy for B-ALL as well as other conditions dependent on IL7R signaling.
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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Apoptosis
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Azepines / therapeutic use*
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B-Lymphocytes / pathology
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation
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Chromatin Immunoprecipitation
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Flow Cytometry
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Gene Expression Profiling
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Gene Rearrangement
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Humans
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Mice
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Mice, Inbred NOD
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Nuclear Proteins / antagonists & inhibitors*
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Oligonucleotide Array Sequence Analysis
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Cytokine / genetics*
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Receptors, Interleukin-7 / genetics
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Receptors, Interleukin-7 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Risk Factors
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Transcription Factors / antagonists & inhibitors*
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Triazoles / therapeutic use*
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Xenograft Model Antitumor Assays
Substances
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(+)-JQ1 compound
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Azepines
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BRD4 protein, human
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Biomarkers, Tumor
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CRLF2 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Receptors, Cytokine
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Receptors, Interleukin-7
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STAT5 Transcription Factor
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Transcription Factors
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Triazoles
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JAK2 protein, human
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Janus Kinase 2