Dissecting the Functional Role of Monocytes in B-cell Acute Lymphoblastic Leukemia Survival

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Scientific Abstract The bone marrow microenvironment most likely plays a significant role in promoting B-cell acute lymphoblastic leukemia (B-ALL) survival, progression, and escape from treatment. Our preliminary studies utilized single-cell profiling approaches to comprehensively map the primary human B-ALL bone marrow immune microenvironment throughout three distinct stages of the disease: diagnosis, remission and relapse. Importantly, we uncovered a role for leukemia-associated monocyte subpopulations in B-ALL survival, demonstrating that monocyte abundance at diagnosis is predictive of pediatric and adult B-ALL patient outcomes. Using a three-dimensional (3D) microfluidics-based organotypic device, we show that human B-ALL blasts alter a vascularized microenvironment to promote monocytic differentiation and depletion of leukemia associated myeloid cells in Ph+ B-ALL animal models leads to prolonged disease remission in vivo. This project will determine the precise origins and function of nonclassical monocytes in supporting B-ALL survival and, ultimately, target leukemia-supporting monocytes to enhance the efficacy of existing ALL therapy. To achieve this, we will use two-photon live-imaging to assess nonclassical monocytes' behavior within the leukemic niche. We will then take advantage of murine strains lacking nonclassical monocytes, as well as established single-cell profiling approaches, to assess monocyte abundance's impact on the remodeling of a vascularized leukemic niche in vivo. We will expand our flow cytometric analysis of large cohorts of primary pediatric B-ALL patient samples to establish the association between monocyte abundance, monocyte differentiation state, and patient treatment outcome through a collaboration with pediatric leukemia experts, Drs. Karen Rabin (Baylor University/Texas Children's Hospital) and Charles Mullighan (St Jude Children's Hospital). Finally, murine and human xenograft pre-clinical in vivo B-ALL platforms to determine the impact of depleting leukemia-supporting monocytes (anti-CSF1R therapy) in combination with conventional B-ALL chemotherapy on B-ALL survival. These findings will ultimately provide the basis for clinical trials combining CSF1R inhibition with existing B-ALL therapeutics. This proposal outlines my career development plan for obtaining the necessary preparation to transition into a successful independent investigator. My postdoctoral supervisor, Dr. Iannis Aifantis, fully supports my distinct research program. My ongoing training with experts in nonclassical monocyte biology (Dr. Hedricks, La Jolla Institute for Immunology), live in vivo two-photon microscopy (David Fooksman, Albert Einstein) and single-cell bioinformatics (Dr. Tsirigos, NYU Applied Bioinformatics Laboratories) will provide the essential knowledge to accomplish my long-term scientific goals. Collectively, the proposed research and career development plans will generate data with a significant impact on immune-based therapies in pediatric leukemia and provide the basis of my future research as an independent researcher.