BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia

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 rea...

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Veröffentlicht in:	Blood Jg. 120; H. 14; S. 2843
Hauptverfasser:	Ott, Christopher J, Kopp, Nadja, Bird, Liat, Paranal, Ronald M, Qi, Jun, Bowman, Teresa, Rodig, Scott J, Kung, Andrew L, Bradner, James E, Weinstock, David M
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 04.10.2012
Schlagworte:	Animals Apoptosis Azepines - therapeutic use B-Lymphocytes - pathology Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Blotting, Western Cell Cycle Proteins Cell Line, Tumor Cell Proliferation Chromatin Immunoprecipitation Flow Cytometry Gene Expression Profiling Gene Rearrangement Humans Janus Kinase 2 - genetics Janus Kinase 2 - metabolism Mice Mice, Inbred NOD Nuclear Proteins - antagonists & inhibitors Oligonucleotide Array Sequence Analysis Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Real-Time Polymerase Chain Reaction Receptors, Cytokine - genetics Receptors, Interleukin-7 - genetics Receptors, Interleukin-7 - metabolism Reverse Transcriptase Polymerase Chain Reaction Risk Factors RNA, Messenger - genetics STAT5 Transcription Factor - genetics STAT5 Transcription Factor - metabolism Transcription Factors - antagonists & inhibitors Triazoles - therapeutic use Xenograft Model Antitumor Assays
ISSN:	1528-0020, 1528-0020
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2012-02-413021