Modeling LSC heterogeneity at unprecedented resolution in AML
Craig Jordan
PhDUniversity of Colorado Denver, Anschutz Medical Campus
Project Term: October 1, 2024 - September 30, 2027
Our goal is to perform high-resolution molecular characterization of human leukemia stem cells (LSCs). We have developed an integrated set of single-cell techniques that will assess transcriptional, genomic, and phenotypic features of primary LSC populations obtained from patients undergoing varying forms of treatment. We expect to create a molecular atlas of primary LSCs that will provide the leukemia research community with a powerful resource for the development of improved therapies.
The blood cancer acute myeloid leukemia (AML) is a devastating disease with very limited treatment options and poor outcomes. While several new therapeutic agents for AML have been developed over the past decade, few have had a significant impact, and the prognosis for most patients is not good. Thus, it is important to understand why current drugs fail and to use such knowledge to devise improved therapies. One potential explanation for the failure of conventional agents lies in the inherent diversity of leukemia cells. Studies in recent years have shown that cells within leukemic populations can vary widely with respect to many properties, including drug sensitivity. In particular, so-called “leukemia stem cells” (LSCs), which are thought to be important for the perpetuation of disease, are often highly drug-resistant. Therefore, strategies designed to better eradicate LSCs are a high priority.
To address the challenge of drug-resistant LSCs, we have developed a very advanced set of laboratory techniques. These approaches allow us to examine molecular events that occur in individual cells. In the current grant application, we propose to use such methods to determine the basic properties of LSCs, in particular, the molecular mechanisms that control drug resistance. Upon completion of the proposed experiments, we expect to have generated a detailed atlas of LSC molecular biology that will be shared with the leukemia research community. We believe these data will provide a powerful resource for all scientists seeking to develop improved therapies for AML.