Functional dissection of oncogenic enhancers T cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of pediatric and 25% of adult T-ALL cases and was originally identified as highly aggressive tumor associated to poor prognosis. Despite recent progress in the treatment of this disease, the prognosis of patients with relapsed and refractory T-ALL remain extremely poor, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective antileukemic drugs. We recently identified N-Me, a NOTCH1-bound enhancer driving MYC expression in T-cells. This enhancer is recurrently amplified in T-ALL and is strictly required for NOTCH1-induced transformation. These results demonstrate a critical role for long-range regulatory sequences in the pathogenesis of NOTCH1-induced T-ALL and highlight the potential for enhancer-driven gene expression mechanisms as a therapeutic target for the treatment of human cancer. Based on our results, we hypothesize that N-Me regulates gene expression in T- ALL by interacting with additional as yet uncharacterized long-range regulatory sequences and via the activity of T-cell lineage specific transcription factors. Moreover, we propose that oncogenic NOTCH1 controls additional key long range enhancers controlling master regulators of the leukemia oncogenic program in addition to MYC and that long range regulatory enhancers play a critical role in the pathogenesis solid tumors. The goal of this proposal is to advance our understanding of the basic mechanisms of long-range transcriptional regulation in human cancer as a first step to ultimately provide new tools and targets for the treatment of this disease. Toward this objective we propose: (i) To analyze the mechanisms of N-Me mediated Myc expression in T-ALL (Aim 1); (ii) To functionally dissect the role of N-Me in the control of Myc expression in vivo using CRISPR/Cas9 genome editing tools (Aim 2); and (iii) To identify NOTCH1-bound enhancers in solid tumors (Aim 3).
N-Me is a NOTCH1-bound MYC enhancer that is critically required for T-cell development and for NOTCH1-induced T-cell leukemia. Our preliminary results show that this oncogenic enhancer is recurrently amplified in human leukemia and is only active in T-cells, underscoring the need to understand what factors confer its T-cell specificity. This project will define the mechanisms of action and regulation of the N-Me enhancer in vivo and will provide novel insights on the basic biology of enhancers and superenhancers, which will ultimately facilitate the development of novel cancer therapies targeting these regions.
|Sanchez-Martin, Marta; Ambesi-Impiombato, Alberto; Qin, Yue et al. (2017) Synergistic antileukemic therapies in NOTCH1-induced T-ALL. Proc Natl Acad Sci U S A 114:2006-2011|
|Fabbri, Giulia; Holmes, Antony B; Viganotti, Mara et al. (2017) Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 114:E2911-E2919|