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Why clonal hematopoiesis?
As we age, some of our blood stem cells can acquire mutations that causes them to expand resulting in the formation of their own distinct “clones”. This condition known as “clonal hematopoiesis” increases the chances of developing blood cancers such as leukemia. If we could identify and prevent such clones from expanding this can dramatically reduce risk for blood cancers. Despite its importance, we still don’t understand why these clones emerge only in some individuals and why only a small subset of such carriers’ eventually progresses to cancer?
Key Questions
Why blood stem cells undergo clonal changes and what are the underlying mechanisms?
How inherited genetic variants influence clonal hematopoiesis and blood cancers?
Does inherited genetic variants interact with cancer mutations?
Functional Genomics of Noncoding Risk Variants
Functional Genomics of Noncoding Risk Variants
Most disease-associated genetic variants occur outside protein-coding regions, making it challenging to identify which variants are functional and how they influence disease risk.
We use massively parallel reporter assays (MPRA) to systematically identify regulatory variants within clonal hematopoiesis risk loci and combine these screens with targeted genome editing and functional studies in hematopoietic cells to determine how noncoding genetic variation alters gene regulation and clonal behavior.
Mechanisms Linking Germline Variation to Hematopoietic Stem Cell Clonal Expansion.
Mechanisms Linking Germline Variation to Hematopoietic Stem Cell Clonal Expansion.
We investigate how genes identified through human genetics regulate hematopoietic stem cell function. Using CRISPR/Cas9 genome engineering in primary human hematopoietic stem and progenitor cells, we dissect the molecular mechanisms through which candidate predisposition genes influence stem cell proliferation, differentiation, and clonal expansion.
Our studies of PURB, a germline predisposition gene associated with clonal hematopoiesis and MDS, reveal connections between stem cell expansion, RNA processing, and R-loop homeostasis.
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