Project Term
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Dana-Farber Cancer Institute
Boston, MA
United States
Project Summary
Acute myeloid leukemia (AML) is subject to macrophage-mediated immune clearance, although the mechanisms remain poorly understood. Using genome-wide CRISPRi screens in AML cells co-cultured with macrophages, we identified new regulators of susceptibility to phagocytosis, including a therapeutically targetable link to RHOA signaling. I will dissect the underlying mechanisms and test combinatorial RHOA and PI3Kγ inhibition to nominate novel treatment strategies that overcome AML immune evasion.
Lay Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer that affects both children and adults. Despite new drugs and intensive chemotherapy, many patients relapse because their leukemia cells escape destruction by the immune system. AML cells can avoid being eaten and destroyed by immune cells called macrophages. Macrophages normally act as “clean-up crew” in the human body by identifying and removing harmful or abnormal cells through a process known as phagocytosis. Current drug strategies designed to boost macrophage phagocytosis have had limited success, highlighting the urgent need to find new ways to make leukemia cells more vulnerable to macrophage attack.
Our research focuses on discovering how AML cells resist macrophage attack and how we can restore this powerful immune response. Using a cutting-edge approach called CRISPR screening, a method to turn off thousands of genes one at a time, we have identified several leukemia cell genes that make them less likely to be engulfed by macrophages. In particular, we found that a signaling molecule called RHOA helps leukemia cells resist phagocytosis. We also discovered that blocking another pathway, called PI3K gamma, makes macrophages more effective at attacking leukemia cells, especially when combined with RHOA inhibition.
We will now study how these two pathways, RHOA and PI3K gamma, control macrophage clearance of leukemia cells. Using human AML cell lines, patient-derived samples, and humanized mouse models, we will rigorously test whether blocking these pathways can increase the ability of macrophages to clear leukemia. Furthermore, we will examine the molecular changes inside leukemia cells that allow them to hide from macrophages, helping us identify new drug targets.
This research will reveal the key ways AML cells evade macrophage-mediated clearance and provide a scientific foundation for new treatment strategies that utilize macrophages to eliminate leukemia. Ultimately, our goal is to improve the effectiveness of immunotherapies for patients with AML and other blood cancers.
Program
Grant Subprogram