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.
The gene encoding the RUNX1 transcription factor is mutated in a subset of T-cell acute lymphoblastic leukemia (T-ALL) patients, and mutations are associated with a poor prognosis. These mutations cluster in the DNA-binding Runt domain and are thought to represent loss-of-function mutations, indicating that RUNX1 suppresses T-cell transformation. RUNX1 has been proposed to have tumor suppressor roles in T-cell leukemia homeobox 1/3-transformed human T-ALL cell lines and NOTCH1 T-ALL mouse models. Yet, retroviral insertional mutagenesis screens identify genes as collaborating oncogenes in MYC-driven leukemia mouse models. To elucidate RUNX1 function(s) in leukemogenesis, we generated mice and examined leukemia progression in the presence of vehicle or tamoxifen. We found that deletion inhibits mouse leukemic growth in vivo and that silencing in human T-ALL cells triggers apoptosis. We demonstrate that a small molecule inhibitor, designed to interfere with CBFβ binding to RUNX proteins, impairs the growth of human T-ALL cell lines and primary patient samples. We demonstrate that a RUNX1 deficiency alters the expression of a crucial subset of TAL1- and NOTCH1-regulated genes, including the and oncogenes, respectively. These studies provide genetic and pharmacologic evidence that RUNX1 has oncogenic roles and reveal RUNX1 as a novel therapeutic target in T-ALL.
1880 Thymic expression of the Tal1 and Lmo2 oncogenes in mice results in rapid development of T-ALL, and similar to T-ALL patients, over half the leukemic mice develop spontaneous mutations in Notch1. We have previously shown that Notch1 inhibition reduces and in some cases eliminates leukemia-initiating cells (L-ICs), however the use of anti-Notch1 therapies in the clinic has been limited due to on-target effects of Notch inhibition in the intestine. Due to the toxicities associated with Notch inhibition in vivo, we hypothesized that it may be more effective to inhibit c-Myc, a critical Notch1-regulated gene in T-ALL. We demonstrate that silencing of c-Myc in primary mouse T-ALL cells significantly prolongs survival by reducing L-IC frequency and self-renewal. A novel bromodomain inhibitor, JQ1, has been developed and shown to inhibit c-Myc in multiple hematopoietic malignancies, but its effects on LSCs or L-ICs remain unclear. Our preliminary studies reveal that JQ1 treatment prolongs survival in our mouse T-ALL model, at least in part, by reducing c-Myc mRNA and protein levels. Whether JQ1 has anti-L-IC activity in mouse T-ALL models and relapsed pediatric T-ALL patient samples will be discussed. Disclosures: No relevant conflicts of interest to declare.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.