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Co-optation of B cell developmental states in malignancy and autoimmunity
Transcriptional states provide a useful lens for understanding the diversity of cell identity and function. Cell state is regulated through both cell-intrinsic and -extrinsic mechanisms, and can diversify through tightly regulated transitions. However, perturbations to these regulatory mechanisms facilitate shifts in cell phenotypes and function that, gone unchecked, can disrupt homeostasis and drive disease. The ability of dysregulated transcriptional states to integratively represent underlying intrinsic and extrinsic drivers of aberrant cell survival and function nominates their potential as prognostic and therapeutic targets in disease.
Here, we establish the therapeutic significance of cell state through the lens of pathologies that dysregulate B cell development and maturation. B cells develop and mature through tightly regulated cell-intrinsic and -extrinsic transcriptional state transitions restricted by stage-specific survival, proliferative, and apoptotic dependencies. We thus utilize B cell development and maturation as model systems to study how perturbations to cell-intrinsic and -extrinsic regulators can result in the pathologic emergence of aberrant developmental states enabling dysregulated survival and proliferation. In each chapter, we apply single-cell RNA-sequencing to define heterogeneous B cell developmental states in malignancy and autoimmunity, and uncover underlying signaling perturbations linked to their dysfunctional transcriptional regulation. We consider how these aberrant developmental states are driven by mutational perturbations to dysregulated cell-intrinsic signaling in BCR-ABL1 B cell acute lymphoblastic leukemia (B-ALL), cell-extrinsic signaling in CTLA4-deficient T cell-mediated follicular B cell blocks, and integrative mutational and niche-specific survival in mantle cell lymphoma (MCL). Finally, we identify how these aberrant developmental states shift or resolve upon targeted therapeutic intervention in each disease context. Collectively, this work demonstrates how cell states are intrinsically and extrinsically regulated, inform aberrant survival in disease, and demonstrate promise as therapeutic targets.
Thesis Supervisor:
Alex K. Shalek, PhD
J. W. Kieckhefer Professor, Institute for Medical Engineering & Science and Department of Chem
Thesis Committee Chair:
Stefani Spranger, PhD
Howard S. and Linda B. Stern Career Development Professor, Associate Professor of Biology
Thesis Reader:
Catherine J. Wu, MD
Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School
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