ETS1-dependent combinatorial control of oncogenic transcription in Notch-activated T-ALL

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The discovery of NOTCH1 as the most prevalent oncogene in T-cell acute lymphoblastic leukemia (T-ALL) patients raised hopes for targeted therapy in this cancer. Unfortunately, in clinical trials, the pan-Notch inhibitor GSI caused dose-limiting toxicities, particularly intestinal, due to abrogation of Notch functions. Our idea to meet this challenge stems from Drosophila studies showing that Notch requires co-binding transcriptional factor partners at its response elements to generate cell-type specific gene expression programs. If these “Notch- collaborating” transcription factors are hijacked to help drive Notch-induced T-ALL, then inhibiting them might oppose Notch signals and circumvent GSI toxicities. Thus, our long-term goal is to identify Notch-collaborating transcription factors and determine their potential as safe, therapeutic targets. In our preliminary data, we show that ETS1 is the top-ranked Notch-associated transcription factor in the context of T cells, but not intestinal cells. Compared to GSI, the effects of Ets1 inactivation were just as deleterious to T-ALL cells but were much milder on intestinal homeostasis and overall health in mouse models. Mechanistically, we show that CDC73, the scaffold component of the polymerase-associated factor complex (PAF1C), binds ETS1 and is recruited to activate ETS1 response elements. One of these elements is a previously unrecognized but highly conserved superenhancer, which we have tentatively labeled “E-Me” for “ETS1-dependent MYB enhancer”. Our objective is to determine the effects of Ets1-dependent trans-factors and cis-elements on the control of oncogenic transcriptional programs in Notch-activated T-ALL. We hypothesize that disrupting the ETS1-dependent combinatorial control of transcriptional elements by targeting CDC73 or the E-Me will safely repress Notch- induced T-ALL. To test this, we will determine the effects of inhibiting Ets1-dependent factors like Cdc73 on leukemia maintenance in mouse and human models of T-ALL. We will also determine the effects of inhibiting Ets1-dependent factors on oncogenic transcriptional programs and cis-element activation. Finally, we will determine the role of the E-Me element where trans-acting factors are recruited by ETS1 to collectively drive the oncogenic MYB effector pathway. Our work raises the possibility of targeting co-binding Notch-collaborating transcriptional regulators like Ets1 that create the chromatin context that directs Notch functions. Here we will establish Cdc73 as the bridge that connects Ets1 to transcriptional machinery and chromatin modifiers that activate promoters and enhancer elements and highlight E-Me as an important example. Therefore, if successful, our project is significant because we target the #1 ranked Notch-associated cofactor in a cancer to disable Notch- driven oncogenic signals without the toxicities of pan-Notch inhibitors seen in clinical trials. This project is innovative because, to our knowledge, no other Notch cofactor besides ETS1 has been shown to physically recruit Notch to chromatin genome-wide with strong statistical and orthogonal rigor and with a strikingly high convergence of Notch cofactor and Notch binding motifs that was validated by chromatin profiling.