Abstract PR02: Targeting NOTCH1 and C-MYC in humanized models of relapsed and induction failure pediatric T-ALL

Abstract

Although prognosis has improved for children with T cell acute lymphoblastic leukemia (T-ALL), 20-30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (L-ICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc and c-Myc is 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 shRNA or pharmacological approaches prevents leukemia initiation in mice by reducing the L-IC population. Consistent with its anti-L-IC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and induction failure (IF) pediatric T-ALL samples in vitro. Although treatment of relapsed T-ALL cells with gamma secretase inhibitors (GSI) or JQ1 reduces, it does not abrogate C-MYC mRNA levels, indicating a role for dual NOTCH and MYC inhibition in relapsed disease. To test this possibility, we engrafted immunodeficient NSG mice with relapsed pediatric T-ALL cells and treated them with vehicle, GSI, JQ1 or with GSI and JQ1 and monitored survival. Although JQ1 or GSI treatment alone significantly prolonged survival, the combination therapy was more effective at extending survival. These findings reveal a requirement for MYC in mouse and human L-IC maintenance and provide evidence that NOTCH1 and MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients. This abstract is also presented as Poster A48. Citation Format: Justine E. Roderick, Jessica Tesell, Alejandro Gutierrez, Thomas Look, Jun Qi, James E. Bradner, Michelle A. Kelliher. Targeting NOTCH1 and C-MYC in humanized models of relapsed and induction failure pediatric T-ALL. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR02.