Current Research and Scholarly Interests
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is rapidly fatal within months if untreated. Even with aggressive treatment, including high dose chemotherapy and bone marrow transplantation, five-year overall survival rates range between 30-40%. A growing body of evidence indicates that not all cells in this cancer are the same, and that there is a rare population of leukemia stem cells (LSC) that are responsible for maintaining the disease. These findings have led to the idea that in order to cure this cancer, the LSC must be eliminated, while at the same time sparing the normal blood forming stem cells within the bone marrow.
The overall goal of our research is to identify molecular and genetic differences between human AML stem cells and their normal counterparts, and then to develop therapeutic strategies directed against these targets. We utilize bioinformatics, genomics, and functional methods to investigate genes and pathways preferentially expressed or activated in LSC. From this analysis, we have identified a number of factors, including several cell surface protein markers that are more highly expressed on AML LSC compared to their normal counterparts. We have focused on one of these markers, CD47, that contributes to leukemia development by blocking the ingestion and removal of leukemia cells by cells of the immune system. Most significantly, we determined that blocking monoclonal antibodies directed against CD47 targeted LSC and depleted leukemia in mouse pre-clinical models. We have now developed a clinical grade humanized anti-CD47 antibody that is in clinical trials at the Stanford Cancer Center.
Our research has also investigated the development of AML from normal blood forming, or hematopoietic, stem cells (HSC). Genomic studies have determined that most cases of AML are associated with an average of 5 mutations, raising the question of how these multiple mutations accumulate in a single lineage of cells. We hypothesized that since HSC are the only long-lived, self-propagating cells in the myeloid lineage, then the mutations must be serially acquired in clones of HSC. Using primary patient samples and single cell genomic methods, we found evidence of pre-leukemic HSC and mutations, confirming our hypothesis. Furthermore, we showed that these pre-leukemic HSC survive chemotherapy and may give rise to relapsed disease. Thus, these pre-leukemic mutations may be critical targets for curative therapies.
