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

Christopher J. Ott, Nadja Kopp, Liat Bird, Ronald M. Paranal, Jun Qi, Teresa V. Bowman, Scott J. Rodig, Andrew L. Kung, James E. Bradner, David M. Weinstock

Research output: Contribution to journalArticle

233 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2843-2852
Number of pages10
JournalBlood
Volume120
Issue number14
DOIs
StatePublished - Oct 4 2012
Externally publishedYes

Fingerprint

Interleukin-7 Receptors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Transcription
Phosphorylation
Genes
Cells
myc Genes
Cytokine Receptors
Cytogenetics
Down-Regulation
Genome
Apoptosis
Cell Line
Survival
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Ott, C. J., Kopp, N., Bird, L., Paranal, R. M., Qi, J., Bowman, T. V., ... Weinstock, D. M. (2012). BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood, 120(14), 2843-2852. https://doi.org/10.1182/blood-2012-02-413021

BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. / Ott, Christopher J.; Kopp, Nadja; Bird, Liat; Paranal, Ronald M.; Qi, Jun; Bowman, Teresa V.; Rodig, Scott J.; Kung, Andrew L.; Bradner, James E.; Weinstock, David M.

In: Blood, Vol. 120, No. 14, 04.10.2012, p. 2843-2852.

Research output: Contribution to journalArticle

Ott, CJ, Kopp, N, Bird, L, Paranal, RM, Qi, J, Bowman, TV, Rodig, SJ, Kung, AL, Bradner, JE & Weinstock, DM 2012, 'BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia', Blood, vol. 120, no. 14, pp. 2843-2852. https://doi.org/10.1182/blood-2012-02-413021
Ott, Christopher J. ; Kopp, Nadja ; Bird, Liat ; Paranal, Ronald M. ; Qi, Jun ; Bowman, Teresa V. ; Rodig, Scott J. ; Kung, Andrew L. ; Bradner, James E. ; Weinstock, David M. / BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. In: Blood. 2012 ; Vol. 120, No. 14. pp. 2843-2852.
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AU - Bowman, Teresa V.

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