Functional evaluation of clonal hematopoiesis of indeterminate potential (CHIP)

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ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of hematopoietic stem cell (HSC) clones with acquired mutations thought to be caused by normal aging or bone marrow stress. People with CHIP clones are at increased risk of developing a blood cancer, cardiovascular disease or ischemic stroke. Our understanding of the pathophysiology of CHIP progression has been limited to large next generation sequencing studies performed in adults. Therefore, the molecular mechanisms and clonal expansion and dynamics in the context of CHIP mutations, are poorly understood. As a postdoctoral fellow in the Obeng laboratory and co-sponsored by Dr. Mitch Weiss, I will study the pathobiological mechanisms of CHIP expansion in pediatric patients and using mouse models. In Aim 1, I will use targeted genomic sequencing to define the incidence and clinical complications of CHIP in a large, well-annotated cohort of pediatric patients. In this aim, I will help define CHIP incidence in poorly studied cohort and expand on my training in computational biology and functional genomics. In Aim 2, I will use molecular barcoding to label and track the clonal dynamics of hematopoietic stem cells (HSCs) expressing different, common CHIP mutations. I will determine how different mutations affect clonal expansion in different HSC compartments and how chronic inflammation and aging affect the behavior of different CHIP clones. In this aim, I will help define how HSC clones harboring CHIP-related mutations expand in vivo. Collectively, these aims draw upon my prior molecular and computational biology experience and provide new training in stem cell biology and functional genomics. The technical and intellectual resources at St. Jude Children's Research Hospital provide the optimal environment for my training. In addition to the exceptional training and access to the state-of-the-art core facilities available at St. Jude, I will also take advantage of numerous career development resources during my fellowship in the form of institutional and outside workshops, networking opportunities, teaching and mentoring opportunities, and seminars. I will have access to a large, well-annotated clinical cohort, well-characterized animal models, and state-of-the-art genome sequencing and flow cytometry facilities. I will work closely with our collaborators in Computational Biology and Biostatistics to learn how to analyze the data generated by my experiments. I will work with experienced, dedicated mentors and will have access to career development opportunities that will help me become an independent investigator. My studies will help define the molecular features that allow CHIP clones to persist and expand in vivo. A better understanding of the pathobiology of CHIP clones will help guide how CHIP progression is monitored and inform therapeutic considerations in patients of all ages.