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c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Justine E. Roderick, Jessica Tesell, Leonard D. Shultz, Michael A. Brehm, Dale L. Greiner, Marian H. Harris, Lewis B. Silverman, Stephen E. Sallan, Alejandro Gutierrez, A. Thomas Look, Jun Qi, James E. Bradner and Michelle A. Kelliher

Key Points

  • c-Myc is required for leukemia-initiating cell maintenance in murine models of T-ALL.

  • c-Myc inhibition prevents the growth of treatment-resistant primary T-ALL patient samples in vitro.

Abstract

Although prognosis has improved for children with T-cell acute lymphoblastic leukemia (T-ALL), 20% to 30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (LICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc, a known regulator of quiescence in stem and progenitor populations, leading us to examine whether c-Myc inhibition results in efficient targeting of T-ALL–initiating cells. We demonstrate that c-Myc suppression by small hairpin RNA or pharmacologic approaches prevents leukemia initiation in mice by eliminating LIC activity. Consistent with its anti-LIC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and IF pediatric T-ALL samples in vitro. These findings demonstrate a critical role for c-Myc in LIC maintenance and provide evidence that MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients.

  • Submitted August 21, 2013.
  • Accepted December 15, 2013.
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