Metabolic Regulation of Leukemic Cell Fate
Stefan Bjelosevic
PhDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
Cell-intrinsic metabolic processes are dysregulated in acute myeloid leukemia (AML) and can act to sustain an oncogenic state of differentiation arrest. Using AML cell lines and patient-derived material grown in sophisticated liquid culture medium that mimics human plasma, we will perform metabolically focused in vitro and in vivo CRISPR-Cas9 screens to reveal metabolic regulators of AML cell fate that can be exploited via dietary or pharmacologic intervention as a novel therapeutic strategy.
Acute myeloid leukemia (AML) is an aggressive blood cancer, defined by build-up of non-functional immature white blood cells in the body. Whilst in recent years several new medicines have been approved for the treatment of AML, many of these are only useful for certain sub-types of disease, and a vast majority of patients still must undergo aggressive chemotherapy; most die within 5 years. One of the crowning achievements in the search for new treatments for AML was the discovery that a drug, called all-trans retinoic acid (a drug similar to vitamin A), can in many cases cure a specific type of leukemia by removing the AML cell maturation block and allowing them to fully mature and then die. This method is less harsh than chemotherapy as AML cells are specifically eliminated whilst normal healthy white blood cells are spared. This project aims to apply this principle more broadly, by searching for metabolites (such as nutrients, vitamins, often taken in the diet) that when removed from the body or increased in amount can trigger the maturation and death of AML cells while sparing normal, healthy white blood cells. To do this, we will manipulate a specialized cell culture growth medium designed to mimic human blood plasma to maximize the chance that our findings will have in-human relevance. Thus, this aspect of the project aims to discover metabolites whose levels we can manipulate either through diet or via drugs, offering a powerful, and previously unexplored, way of treating AML that is significantly less harsh than chemotherapy (thus offering considerable quality-of-life improvements to AML patients). In parallel to these efforts, we will utilize a bespoke methodology to find metabolic proteins that control the maturity of AML cells. This methodology involves systematically deleting genes in these cells and observing if their deletion in turn allows leukemia cells to mature. This strategy has the potential to therefore identify targets that can then be inhibited themselves (with drugs) to trigger AML cell maturation. We believe that these complementary approaches maximize the chances of discovering metabolic pathways that we can exploit for therapeutic benefit. Given the poor outcomes faced by patients afflicted with this disease, lack of improvement in long-term survival for many, and the aggressive and debilitating chemotherapy regimens many patients undergo, this project aims to address a critical and unmet clinical need.