C-Myc Inhibition Targets the Leukemia-Initiating Cells in a Tal1/Lmo2 mouse Model of T-ALL

Abstract 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.