title: c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells.
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.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA;
authors.forename: Justine E
authors.initials: JE
authors.lastname: Roderick
authors.forename: Jessica
authors.initials: J
authors.lastname: Tesell
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Marian H
authors.initials: MH
authors.lastname: Harris
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D020868:Gene Silencing; D006801:Humans; D060828:Induction Chemotherapy; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering