L-2-Hydroxygluatarate (L-2HG) as a Metabolic Regulator of Normal and Malignant Hematopoiesis
Abstract
PI Career Goals: Cancer cells rapidly uptake and metabolize sugars, amino acids, fats, and other nutrients to provide building blocks and signals that support malignant cell growth and division. Because cancer cells metabolize nutrients differently from normal cells, cancer cell metabolism represents a potential Achilles heel to target with anti-cancer therapies. During my graduate career, I plan to investigate how dysregulated metabolism drives blood cancer initiation and progression and how it can be targeted to better treat blood cancers. The Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Horizon Award will allow me to advance my career aspirations to design novel therapeutic targets for blood cancers. My researcher development plan outlines an appropriate timeline, approach and resources to achieve my career goals. Scientific Objective & Rationale: Blood stem cells are responsible for replenishing the entire blood supply after significant blood loss caused by injuries, radiation, and toxins. Blood stem cells live in a low oxygen environment in the bone marrow. This low oxygen environment or “niche” has various components that allow blood stem cells to balance the ability to renew themselves, as well as make progeny that develop into mature white blood cells, red blood cells, and platelets. Although some features of the blood stem cell niche environment have been elucidated, the blood stem cell niche still remains poorly understood, making it impossible to maintain blood stem cells outside of humans/animals. Understanding these niche components further will elucidate the mechanisms of blood stem cell maintenance and improve the ability of blood stem cells to replenish the blood supply. An important goal of this proposal is to determine whether a metabolite (L-2HG) produced by blood stem cell is important for maintaining their stem cell function to allow for effective self-renewal and blood regeneration. Blood cancers result from a combination of uncontrolled growth of abnormal blood cell stem cells and an impaired ability of blood stem cells to develop into mature blood cells. A common and highly lethal form of blood cancer is acute myeloid leukemia (AML), which results from the rapid growth of abnormal immature white blood cells. AML destroys the body’s ability to make normal white blood cells, red blood cells, and platelets, causing infection, anemia, and bleeding, respectively. Because exposure to radiation and chemical toxins are risk factors for development of acute myeloid leukemia, military personnel, and Veterans are at increased risk of developing this deadly form of blood cancer. Moreover, active duty Service members and Veterans diagnosed with blood cancers exhibit decreased survival rates in comparison to civilians. Standard therapies for AML include chemotherapy and allogenic stem cell transplant, but outcomes remain poor with less than 50% of patients alive 5 years after diagnosis. We have identified a small metabolite called L-2HG which is produced by normal blood stem cells and overproduced leukemia cells. Our data suggest that this metabolite may be important for regulating the function of normal blood stem cells and that deregulation of this metabolite may contribute to leukemia. We plan to dissect the importance of this metabolite for normal blood stem cells and determine whether this metabolite can be targeted to treat acute myeloid leukemia. Based on this plan, our research falls under the FY19 PRCRP Topic Area of Blood Cancers impacting the gaps in cancer prevention, and improving treatment of blood cancers. The proposed research will also improve our understanding of how exposure to environmental risk factors, such as radiation and chemical toxins, impacts blood stem cell function and contributes to development of blood cancers. Ultimately, our research seeks to help all patients suffering from AML, improve allogenic stem cell transplant therapy, and improve survi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010425
Entities
People
- Sylvia Zohrabian
Organizations
- United States Army
- Weill Cornell Medicine