c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells
Department of Cancer Biology; Program in Molecular Medicine
Medical Subject Headings
Animals; Antineoplastic Agents; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Child; Gene Silencing; Humans; *Induction Chemotherapy; Mice; Mice, Transgenic; Neoplastic Stem Cells; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; Recurrence; Treatment Failure
Cancer Biology | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology
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.
Rights and Permissions
Citation: Blood. 2014 Feb 13;123(7):1040-50. doi: 10.1182/blood-2013-08-522698. Epub 2014 Jan 6. Link to article on publisher's site
DOI of Published Version
Roderick, Justine E.; Tesell, Jessica M.; 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.; and Kelliher, Michelle A., "c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells" (2014). GSBS Student Publications. 1909.