Dissecting the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis

Rong Lu

PhD

University of Southern California

Project Term: July 1, 2019 - June 30, 2024

Project Summary

Our group has developed a novel technology to track individual cells in mice and to identify the rare cells that drive clonal expansion. Clonal expansion is the excessive increase in the descendants of a cell. It is thought to play a crucial role during the early stages of blood cancer formation. Clonal expansion is often initiated by rare molecular events, such as mutations in genes and changes in how genes are regulated. These molecular events can increase the opportunities for accumulating additional molecular events that eventually lead to cancer. Clonal expansion can be easily monitored by periodically sampling the blood. This approach may indicate the onset of cancer. However, not all instances of clonal expansion lead to blood cancer. For example, clonal expansion is frequently observed in the elderly that are free of any apparent diseases. Recently, studies from our group and others have shown that clonal expansion also commonly occurs after bone marrow transplantation. Little is known about the differences between normal and cancer-associated clonal expansion, particularly with respect to the precise cellular and molecular mechanisms that drive clonal expansion to initiate cancer. This knowledge gap largely results from difficulties in identifying and studying rare cancer-initiating cells. Our approach overcomes the technical barriers associated with the study of clonal expansion. We use genetic barcodes to tag each cell with a unique identifier that can be tracked at any time. Sequencing these barcodes and all the transcribed genes in each of these cells provides the opportunity to understand which genes are important in the cells that are involved in clonal expansion. From this analysis, we will identify the genes that play key roles in acute lymphoblastic leukemia (ALL) onset and relapse. We will dissect clonal expansion using both mouse models and human patient samples. We will also study leukemia relapse using primary human ALL cells obtained from patients upon initial diagnosis and relapse, and we will use the same approach to identify the molecular events leading to hematopoietic stem cell expansion in otherwise healthy individuals, which may identify those who are more likely to eventually develop cancer. In contrast to conventional studies that analyze cell mixtures, our research uniquely probes the specific cells that drive the development of leukemia. We expect to identify the key cellular and molecular events that drive leukemia onset and relapse. These findings will help improve cancer diagnosis and can serve as new therapeutic targets for treating leukemia.