Runx1 mutations in the pre-leukemic stem cell

About the Project

E9Runx1 function is absolutely essential for the formation of HSCs in the embryo, but once HSCs colonize the fetal liver they are no longer exquisitely Runx1 dependent (Chen et al. Nature 2009, Tober et al. Development, 2013). However, HSCs containing loss of function (LOF) Runx1 mutations are not normal – they are preleukemic stem cells (pre-LSCs) that are targets for secondary mutations. LOF RUNX1 mutations are common in multiple hematopoietic malignancies including acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia, and in the preleukemic myelodysplastic syndrome.

We are examining the functional consequences of Runx1 LOF mutations, both at a cellular and molecular level. An important discovery was that ribosome biogenesis is decreased in Runx1 deficient HSCs, and that this results in resistance of HSCs to endogenous and genotoxic stress. Ribosome biogenesis in HSCs appears to be directly regulated by Runx1, as Runx1 occupies 80% of ribosome gene promoters and the rDNA gene. We are currently studying how secondary mutations cooperate with Runx1 LOF mutations to regulate ribosome biogenesis, and to contribute to leukemia progression.

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