Modeling and targeting leukemic transformation of human hematopoietic stem cells
Sergei Doulatov
PhDUniversity of Washington
Project Term: July 1, 2023 - June 30, 2028
Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.
The Doulatov laboratory is working to understand how genetic mutations transform healthy blood-forming stem cells into leukemias. While enormous advances have been made from modeling blood cancers in mice, we need to understand how mutations work together in human stem cells. This is especially urgent because the current treatments often fail to eradicate mutant stem cells, allowing them to grow back after treatment stops and leading to relapse. My laboratory uses CRISPR-based gene editing to genetically manipulate normal or malignant stem cells from donors. Because donor stem cells are in limited supply, we also “reprogram” patient cells into pluripotent stem cells to create a renewable source of patient-derived blood cells. We have applied these technologies to study two different types of blood cancers. The first one is a myelodysplastic syndrome with mutations in a gene called SF3B1. It usually has a good prognosis, but with additional mutations it can transform into a leukemia. Drugs that target SF3B1 have been developed, but did not lead to durable remissions in a clinical trial. We are investigating if these drugs can target stem cells and working on ways to improve treatment. The second type of cancer we study is an aggressive leukemia with mutations in a gene called TP53, the most frequently mutated gene in cancers. In addition to TP53, most of these leukemias acquire deletions of a small fragment of chromosome 5q. My lab has identified a gene deleted in this piece of chromosome 5q called Lamin B1 that may contribute to the progression of leukemia. We are studying how these leukemias arise and exploring drugs that target 5q deletions or lamin B1. For both of these projects, our goal is to develop therapies that target malignant stem cells to eradicate cancer at its root while sparing healthy stem cells -- leading to lasting remissions.