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 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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Christopher J
CJ
Ott
Nadja
N
Kopp
Liat
L
Bird
Ronald M
RM
Paranal
Jun
J
Qi
Teresa
T
Bowman
Scott J
SJ
Rodig
Andrew L
AL
Kung
James E
JE
Bradner
David M
DM
Weinstock
D000818:Animals; D017209:Apoptosis; D001381:Azepines / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000235:genetics*; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D053614:Janus Kinase 2; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C498762:CRLF2 protein, human; C507924:JAK2 protein, human