Deciphering the intrinsic and extrinsic mechanisms shaping aging and leukemic evolution of hematopoietic stem cells at the single cell level

ended

Clonal Hematopoiesis (CH) is an age related state in which a single and genetically defined Hematopoietic Stem Cell (HSC) contributes more than expected to the hematopoietic pool, due to the selective advantage conferred by genetic variants termed preleukemic mutations (pLMs). CH is a significant risk factor for hematological malignancies such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Today, the mechanisms by which pLMs provide selective advantage and why in some cases clones become leukemic is not fully understood. This project focuses on understanding the dynamic changes that occur in human HSCs in aging and disease at the single cell level. Specifically, we wish to answer the following questions: 1) What are the functional consequences of aging on peripheral blood HSCs 2) what are the functional consequences of pLMs in CH, but also in AML and MDS in humans? 3) which microenvironmental factors provide selective advantage to the mutated clones? To answer these questions, we aim at developing a new innovative approach that will allow us to interrogate thousands of single HSCs from young/old/CH/AML/MDS patients to extract their genotype and their dynamic expression profiles at different time point of differentiation, under different culture conditions. This project will be performed in the Weizmann Institute, one of the world’s leading multidisciplinary basic research institutions in the natural and exact sciences. It will be highly interdisciplinary as it will involve collaboration with renown researchers from the Computer Science and the Chemistry department. In addition to the knowledge acquired in the lab and through the different collaborations, the fellow will benefit from high level training through attendance of various courses, seminars and international conferences. Overall, this project should have great benefit for the career of the fellow.