Aberrant LZTR1 and RIT1 signaling as a driver of clonal hematopoietic disorders
Sisi Chen
PhDMemorial Sloan Kettering Cancer Center
Project Term: October 1, 2021 - September 30, 2024
Our research focuses on a novel mechanism of RAS protein regulation via the protein LZTR1, which is altered in leukemia and hinders the effectiveness of leukemia therapies. We will utilize mouse models and functional genomic studies to uncover how altered RAS degradation drives leukemia and identify novel drug targets. This effort will help us identify the clinical impact of alterations in this novel RAS pathway in patients and potential means to improve leukemia treatment.
Therapeutic approaches targeting altered signaling pathways have resulted in some of the most successful FDA-approved treatments for leukemia patients. For example, the drug Gleevec inhibits the ABL signaling pathway which is responsible for the disease CML (chronic myelogenous leukemia). Similarly, the drug Rydapt inhibits FLT3 signaling which underlies leukemia development in nearly 1/3 AML (acute myeloid leukemia) patients. Despite these advances, one challenge to the success of these targeted therapies is the development of resistance to these drugs. Recently, the levels of the protein LZTR1 was found to regulate the effectiveness of several successful leukemia therapies that inhibit signaling pathways, including the ABL and FLT3 inhibitors mentioned above. This occurs because LZTR1 targets RAS proteins for degradation in the cell’s waste disposal machinery. This was a very important discovery as RAS proteins control cell growth and are some of the most commonly mutated proteins in cancer. In fact, many millions of dollars have been spent to discover drugs to control RAS signaling. Thus, the discovery that LZTR1 can control the abundance of RAS proteins is extremely important. Interestingly, in parallel to this discovery about LZTR1’s function, it was found that LZTR1 and some of the RAS proteins it regulates are mutated in AML and related forms of leukemia. For example, mutations in a poorly studied RAS protein known as RIT1 were recently found in AML. These mutations prevent RIT1 from being degraded by LZTR1, which may lead to more leukemic cell growth. However, there has never been a study of the effect of LZTR1 on leukemia development nor have there been studies on the effect of RIT1 mutations in leukemia. To remedy this knowledge gap, we propose a detailed study of LZTR1 and RIT1 signaling in leukemia. We have developed a series of mouse models for deletion of LZTR1 or RIT1 or expression of leukemia-associated mutations in RIT1 in hematopoietic cells. Further, we have begun to identify proteins beyond the RAS family which are also regulated by LZTR1. Some of these new LZTR1-controlled proteins are also important cancer drug targets. Given the importance of LZTR1 regulation of pathways targeted by several cancer treatments, understanding the precise function of this signaling pathway in leukemia could have major implications for therapy of CML, AML, and other forms of leukemia.