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

• Published in: Blood 2014-02, Vol.123 (7), p.1040-1050
• Main Authors: Roderick, Justine E., Tesell, Jessica, Shultz, Leonard D., Brehm, Michael A., Greiner, Dale L., Harris, Marian H., Silverman, Lewis B., Sallan, Stephen E., Gutierrez, Alejandro, Look, A. Thomas, Qi, Jun, Bradner, James E., Kelliher, Michelle A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Child; Gene Silencing; Humans; Induction Chemotherapy; Lymphoid Neoplasia; Mice; Mice, Transgenic; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Recurrence; RNA, Small Interfering - pharmacology; RNA, Small Interfering - therapeutic use; Treatment Failure
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-08-522698

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. •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.