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Protection of proliferating B lymphocytes from transformation by a c-MYC-induced tumor suppressive program

Takeshi Egawa

Takeshi Egawa


Washington University School of Medicine in St. Louis

Project Term: July 1, 2017 - June 30, 2022

Our research focuses on defining mechanisms by which genes with essential function in normal cells turn to causative drivers of leukemia and lymphomas. Specifically, we study the gene named c-MYC, which is essential for normal cells but causes cancers. We combine genome-wide studies of patient samples and genetic studies in mouse models and identified genes deregulated in MYC-driven cancers. They can be used as biomarkers to identify high-risk patients and potentially targeted for therapies.

Lay Abstract

Lymphomas and leukemias are caused by uncontrolled proliferation of lymphocytes due to accumulating errors in the genome. However, cell proliferation is also an important biological activity across many different tissues and cell types. Specifically, proliferation of lymphocytes is essential for the immune responses that protect individuals from invading pathogens. Normal lymphocytes are able to proliferate even quicker than cancer cells in response to infection for extended periods of time. In the course of normal immune system development, lymphocytes also mutate their own genome to establish better immunity to infection. However, it is unknown how lymphocytes undergo normal proliferation and mutation events without increasing the risk of cancers. We hypothesize that lymphocytes engage an unidentified, unique mechanism to minimize the risk of cancers while facing the demand to proliferate and mutate their genome during their normal functional activities. To explore this hypothesis, we have studied sets of genes that are activated by a protein named c-Myc, which has been causally linked to many cancers in humans and other organisms. Since c-Myc is also essential for lymphocyte proliferation in response to infection, c-Myc may activate an unidentified pathway that is required to protect normally proliferating lymphocytes from becoming cancerous. Accordingly, mutations of genes in the pathway may increase the risk of lymphomas or leukemias. Indeed, we have identified a gene that is activated by c-Myc in proliferating lymphocytes and is necessary to suppress blood cancer development in an animal model. Moreover, a few mutations of this gene have been found in leukemic cells from human patients. Starting with these discoveries, we will define the molecular mechanisms by which this c-Myc initiated regulatory pathway suppresses leukemia and lymphoma. The knowledge from this study will contribute to the development of improved strategies for the risk assessment and diagnosis of leukemias and lymphomas and also to inventing new therapeutic approaches.

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