Taishi Yonezawa, PhD, Postdoctoral Fellow Baylor College of Medicine Area of Research: All Cancers, Lung Cancer Certain somatic mutations result in clonal expansion of mutated hematopoietic cells. This phenomenon, clonal hematopoiesis (CH), accelerates with age and is associated with an ~11-fold increased risk of hematopoietic malignancies and all-cause mortality. Chronic inflammation has been shown to contribute to CH. A recent clinical study suggested that one of the most common genetic mutations in CH and hematopoietic malignancy patients, ASXL1 mutant (MT), is strongly associated with cigarette smoking. Moreover, ASXL1 MT was reported to enhance chronic inflammation. However, the mechanisms linking ASXL1 MT, smoking, and inflammation are not fully understood. In this study, Dr. Yonezawa will use Asxl1 MT transgenic mice and nanoparticle carbon black treatment, which mimics smoking and chronic inflammation, to elucidate the mechanisms through which smoking and the innate immune system contribute to CH progression. Dr. Yonezawa’s proposed study may establish a new therapeutic approach for hematopoietic neoplasms and control of the inflammation induced by ASXL1 MT and smoking.Secondly, as a previous study indicates, ASXL1 MT interacts with the deubiquitinating enzyme BAP1 to induce hematopoietic malignancies. Inhibiting this interaction may be a good therapeutic target for CH and hematopoietic malignancies. Here, Dr. Yonezawa aims to establish for the first time a treatment for ASXL1 MT by identifying ASXL1MT-BAP1 inhibitors using virtual screening. If successful, a ASXL1MT-BAP1 inhibitor could be used to control (and potentially prevent) inflammation and hematopoietic malignancies in patients. The proposed project will dissect the effects of cigarette smoking on CH and chronic inflammation, with the goal of identifying potential treatment candidates for hematopoietic malignancies. Projects and Grants Dissecting how nanoparticles of carbon black in cigarette smoke impact clonal hematopoiesis and inflammation Baylor College of Medicine | Lung Cancer, All Cancers | 2023 | Margaret Goodell, PhD
