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A polymorphism in a promoter explains a mystery of the blood

Siddhartha Jaiswal, Ludwig Cancer Research Stanford
Siddhartha Jaiswal

Mutations that accumulate in hematopoietic stem cells (HSCs) can, when they hit any of a variety of driver genes, boost the fitness of select cells so that their daughters come to dominate the bone marrow niches in which HSCs reside. This leads to a condition known as clonal hematopoiesis of indeterminate potential (CHIP), in which cells derived from such mutants ultimately predominate in the blood. These cells can be precursors for blood cancers—and have also been linked to a host of chronic diseases, including cardiovascular and liver disease—but the basis of their fitness advantage has long been a mystery. To solve that mystery, researchers led by Ludwig Stanford’s Siddhartha Jaiswal developed PACER, a new method to infer the expansion rate of clones from a single time point, and applied it to more than 5,000 samples from people with CHIP. They reported in an April paper in Nature their identification of a common inherited polymorphism in the TCL1A promoter that is associated with a slower expansion rate in clonal hematopoiesis overall. While normal HSCs did not express TCL1A, certain mutations led to aberrant expression of the gene and clonal expansion, but this was blocked by the protective polymorphism. The findings suggest that the fitness advantage of several commonly mutated driver genes in clonal hematopoiesis may be mediated by TCL1A activation and that TCL1A may be a viable target for the treatment of CHIP.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis
Nature, 2023 April 12

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