Programming macrophage-mediated hematopoietic surveillance for precision targeting of AML

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects adults. While many patients respond to treatment, 30-40% experience relapse, emphasizing the urgent need for new and more effective therapies. Our immune system has specialized quality control inspectors called macrophages that surveil blood stem cells and select healthy cells while engulfing unhealthy ones. Macrophages identify and phagocytose unhealthy cells by detecting the ‘eat me’ signal Calreticulin (CALR) on their surface. My research focuses on leveraging this natural quality control mechanism to combat AML. Through a chemical screen, I discovered that inhibiting Src Family kinases (SFKs) causes an increase in cell surface CALR in AML cells without impacting healthy cells. SFK inhibitor (SFKi)-treated AML cells were selectively phagocytosed by macrophages in a co-culture assay compared to healthy stem cells. I hypothesize that modulating SFK activity in AML cells will enhance surface presentation of CALR, thereby promoting their recognition and clearance by macrophages. In my project, I aim to define the intracellular signaling and trafficking mechanisms by which SFKi promotes CALR surface localization on AML cells using phosphoproteomics. I will also assess the therapeutic specificity, effectiveness, and immune-stimulatory potential of SFKi treatment in zebrafish and murine transplant models, measuring leukemia burden, macrophage activation, and phagocytosis. Success will be indicated by identifying a novel phosphorylation pattern on chaperone proteins that perturbs the translocation of CALR from the endoplasmic reticulum to the cell surface in AML. Functional success will be demonstrated by the macrophage recognition and phagocytosis of AML cells in immunodeficient mice transplanted with genetically diverse AML cells, as well as in AML zebrafish models after SFKi treatment. My proposed research combines stem cell biology with macrophage-based strategies, investigating the CALR–SFK signaling axis—an uncharted area with the potential to unlock a new immunotherapy. In the long term, my work aims to develop targeted, less toxic macrophage-based immunotherapies that can prevent relapse, improve survival, and provide safer, more effective treatment options for patients with AML and other blood cancers.