Project Term
–
Stanford University
Stanford, CA
United States
Project Summary
Clonal hematopoiesis (CH) predisposes to hematologic malignancy, but mechanisms are unclear. We identified germline variants at an HSC-associated THRB locus that protect against CH, implicating thyroid hormone signaling in clonal expansion. Using CRISPR perturbation, xenotransplantation, and multi-omics profiling of human HSCs, I aim to define how THRB is regulated and functions in clonal expansion and leukemic progression, revealing targets for prevention and treatment of myeloid malignancies.
Lay Abstract
Blood cancers often begin with subtle changes in the stem cells that make our blood. Throughout life, these blood-forming stem cells naturally acquire changes in their DNA. Most of these changes are harmless, but some allow a small group of stem cells to grow and multiply faster than others. When this happens, that cell and its descendants can take over a large portion of the blood system. This condition is called clonal hematopoiesis. When it occurs in people who do not have a diagnosed blood cancer, it is known as clonal hematopoiesis of indeterminate potential, or CHIP. CHIP becomes more common as we age, and people with CHIP have a higher chance of developing leukemia or other blood cancers. However, we still do not understand why some individuals with CHIP eventually progress to disease.
One of the genes most commonly changed in CHIP is called TET2, which is thought to help mutated stem cells expand. However, changes in TET2 alone do not explain why cancer develops in only some cases. To explore additional factors, we studied inherited DNA differences in more than 400,000 individuals. We identified a DNA change near a gene called thyroid hormone receptor beta (THRB) that is strongly associated with CHIP involving TET2 changes. Notably, individuals who carry this inherited DNA change appear to have a lower risk of developing serious blood cancers. Early results suggest that this DNA region may reduce activity of the THRB gene in blood-forming stem cells.
THRB helps cells respond to thyroid hormone, which regulates metabolism and energy use throughout the body, but its role in blood development is almost completely unexplored. This discovery raises a new possibility: thyroid hormone signaling may influence whether mutated blood stem cells grow harmlessly or progress toward cancer. My research will determine whether the inherited DNA change regulates THRB, investigate how THRB affects stem cell growth, and test whether altering thyroid hormone signals can slow or prevent harmful clonal expansion.
If successful, this research will reveal how THRB and inherited genetic factors shape the earliest stages of blood cancer development. Understanding these early events may help identify which individuals with CHIP are most likely to progress to disease. In the long term, these insights can inform future efforts to develop targeted treatments that block the transition from precancerous stem cell expansion to blood cancers such as leukemia.
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