Evaluating a novel collaboration between NOTCH1 and MLL1 for improved targeted treatments in T-ALL
University of Colorado Denver, Anschutz Medical Campus
Project Term: January 1, 2021 - December 31, 2023
Most T cell acute lymphoblastic leukemia (T-ALL) patients respond to chemotherapy, however many relapse with limited therapy options. To address this problem, we are utilizing a newly-developed human T-ALL system to study two potential therapy targets (NOTCH1 and MLL1) and their interaction, to determine if they can be co-inhibited to eradicate disease. Since compounds that inhibit NOTCH1 and MLL1 are already in development, this novel combination strategy could lead to clinical approval sooner.
Although most patients with T-cell acute lymphoblastic leukemia (T-ALL) initially respond to chemotherapy, approximately half subsequently relapse, particularly those with tumor cells found in the central nervous system. Our aim is to identify new treatment strategies that would either prevent relapse or successfully treat relapsed disease. A majority of T-ALL patients overproduce a protein called NOTCH1. Drugs that inhibit NOTCH1 have been tested in clinical trials but have unacceptable toxicity and side effects. To overcome this, we sought to identify new compounds that can be combined with NOTCH1 inhibitors that would increase effectiveness and reduce toxicity. We made the novel observation that a key gene regulator, MLL1, can collaborate with NOTCH1 in T-ALL. Using genetically-engineered mouse models that reproduce T-ALL in the laboratory, we tested whether modifying MLL1 levels can change the outcome of experimentally-induced NOTCH1¬-activated T-ALL. We found that increasing MLL1 makes NOTCH1-activated T-ALL cells more potent, while decreasing MLL1 delays the onset of T-ALL. A novel feature of our proposed studies is that we will use a newly-developed model in which we produce T-ALL cells from human umbilical cord blood in the laboratory, extending our mouse model findings to human cells. This unique model will enable us to perform in depth characterizations of human MLL1 and NOTCH1 interactions using a variety of genetic and biochemical assays. Results from these studies will tell us how these genes exert their activity to enhance T-ALL and will allow us to identify additional drug targets by revealing the mechanisms of MLL1 and NOTCH1 cooperation. To begin to move these discoveries from the bench to the bedside, we will test drugs currently in clinical trials to block MLL1 or NOTCH1 to determine their combinatorial efficacy. By using this approach, the path towards clinical application is potentially shorter and the benefit for T-ALL patients may be achieved sooner. This detailed characterization of MLL1 and NOTCH1 interplay may result in an innovative and much-needed treatment strategy for T-ALL patients, particularly for those experiencing disease relapse.