Investigating the Role of High Fat Diet in Hematopoiesis and Clonal Hematopoiesis - PROJECT SUMMARY: Aging of the hematopoietic system is accompanied by increase in proliferation but functional decline of hematopoietic stem cells (HSCs), which often exhibit a bias towards myeloid lineage differentiation. These changes are thought to be clinically significant, contributing to age-associated declines in immune function in the elderly. It has been recently discovered that some aged HSCs accumulate somatic mutations that are commonly found in myeloid malignancies. HSCs and progenitors (HSPCs) with these mutations exhibit increased contribution to the blood, a condition termed clonal hematopoiesis (CH). Somatic mutations in CH are recurrently found in about 20 genes, with DNMT3A, TET2 and ASXL1 the top three genes most frequently seen in patients. In clonal hematopoiesis of indeterminate potential (CHIP), a clonal, somatic mutation that is associated with myeloid malignancies is detectable in the peripheral blood at a variant allele fraction of at least 2%. CHIP mutations are found in about 10% of people who are 65 or older but have no obvious signs of blood disease, and the incidence goes up by 6% every 10 years of age. These individuals carry a 1% annual risk of transformation to myeloid diseases such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Additionally, they are associated with increased risk of other important age associated diseases. While CH is clearly a predisposing condition to MDS and AML, not all CH leads to myeloid disease. The factors that promote CH progression to myeloid diseases remain to be elucidated. Mutations of TET2 are commonly found in CH and the same mutations have been identified in myeloid malignancies, including MDS, chronic myelomonocytic leukemia (CMML), and AML. Tet2 inactivation in mice leads to an indolent myeloid neoplasm and the Tet2 knockout (KO) mice exhibit enhanced HSC self-renewal at the stage when the mice show no sign of blood disease, therefore recapitulating many key features of CHIP. Our preliminary studies showed that high fat diet (HFD) exposure in Tet2 knockout mice lead to dysregulation of HSPCs and accelerates myeloid expansion, extramedullary hematopoiesis, and the development of myeloid malignancies. We hypothesize that high fat diet promotes leukemic transformation of clonal hematopoiesis. The main objective of this proposal is to elucidate the mechanistic links between HFD and CHIP, using Tet2 KO model, to identify the mechanism underlying the effects of HFD on clonal hematopoiesis. We will determine the HSPC and other hematopoietic populations that are dysregulated by HFD in Tet2 KO. Our studies identified MHC-II signaling as dysregulated in Tet2 knockout mice fed on HFD. We will elucidate the function of MHC-II signaling in Tet2 KO driven clonal hematopoiesis. Our studies will establish a model of age-related clonal hematopoiesis and its progression to myeloid diseases, and provide new insights into the mechanisms by which dietary factors interact with epigenetic regulators in CH. The work may identify novel targeted strategies to risk stratifying and preventing progression of CHIP to MDS and other myeloid neoplasms.
