Investigating the impact of dysregulated inflammation in interferonopathy on hematopoiesis

ongoing

Hematopoietic stem cells (HSCs), mostly quiescent cells in the bone marrow (BM), are essential throughout life because they are responsible for the continuous production of blood cells. They are of major clinical significance in the context of transplantation for hematological malignancy and the treatment of genetic hematological diseases. Despite major advances in our understanding of the biology of the blood system, understanding the progression of normal versus malignant hematopoiesis, clonal hematopoiesis (CH) or immune disorders is still challenging. My proposal is based on the finding that unbalanced tonic interferon signaling (TIS) emanating from the microbiome in vivo, accelerates the progression of myeloproliferative diseases induced by mutation of the hematopoietic tumor suppressor Tet2. Moreover, another component of TIS, called basal TIS is a fundamental mechanism underlying physiological HSC aging. In this proposal, I would like to explore the role of dysregulated inflammation, as in the case of interferonopathies, on hematopoiesis and hematopoietic stem and progenitor cell (HSPC) biology. I will use advanced molecular tools and technologies and a novel zebrafish model developed within this porposal. I hypothesize that understanding the interplay between chronic IFN activation on the HSCs and progeny over time could be crucial for developing effective treatments and improving outcomes for patients with these challenging disorders. This project will provide incisive insight into the biology of stem cells and into the role of inflammation on hematological malignancies.