Matthew Walter, M.D.
2015 Grant Recipient
Molecular and Phenotypic Tumor Burden Monitoring in MDS
Basic Science Research Grant 2015
Our current ability to predict which patients with MDS will respond to chemotherapy and who will progress to leukemia is limited. Often, rare MDS cells can survive in a patient during or after treatment but are below the level of detection. These rare MDS cells can come back later, leading to relapse. We do not know the best way to monitor for the presence of these rare cells. We are testing in the same samples whether sequencing or flow cytometry is more sensitive to detect and monitor the level of tumor cells in MDS patients during treatment. The goal is to determine whether either approach can detect the growth of rare MDS cells before a patient progresses.
We have enrolled MDS patients in a clinical trial and banked serial bone marrow and blood samples for tumor burden monitoring studies. We have performed prospective flow cytometry analysis to monitor tumor burden in patients and isolated different cell types from fresh bone marrow samples for sequencing. We have also used DNA sequencing to identify DNA mutations in tumor cells and define the number of distinct tumor clones present in samples. We are integrating the results from these studies to determine the best approach to measure tumor burden in MDS patients. We are tracking changes in the fraction of tumor cells present in MDS samples during treatment. We will also compare the ability to monitor tumor burden in peripheral blood versus bone marrow samples, potentially allowing for a less invasive method to monitor a patient’s response to treatment.
Shirai CL, Ley JN, White BS, Kim S, Tibbitts J, Shao J, Ndonwi M, Wadugu B, Duncavage EJ, Okeyo-Owuor T, Liu T, Griffith M, McGrath S, Magrini V, Fulton RS, Fronick C, O’Laughlin M, Graubert TA, Walter MJ. Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell. 2015, May 11;27(5):631-43. PMID: 25965570/PMCID: PMC4430854.
Cara Lunn Shirai, Brian S. White1, Manorama Tripathi1, Roberto Tapia, James N. Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver1, Borja Saez, Robert S. Fulton, Catrina Fronick, Michelle O’Laughlin, Chandraiah Lagisetti, Thomas R. Webb, Timothy A. Graubert & Matthew J. Walter. Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nature Communications 2017, Jan 9, 2017, DOI: 10.1038/ncomms14060.
Eric J. Duncavage, M.D., Meagan A. Jacoby, M.D., Ph.D., Gue Su Chang, Ph.D., Christopher A. Miller, Ph.D., Natasha Edwin, M.D., Jin Shao, M.S., Kevin Elliott, B.A., Joshua Robinson, B.A., Haley Abel, Ph.D., Robert S. Fulton, M.S., Catrina C. Fronick, B.S., Michelle O’Laughlin, B.S., Sharon E. Heath, Kimberly Brendel, B.S., Raya Saba, M.D., Lukas D. Wartman, M.D., Matthew J. Christopher, M.D., Ph.D., Iskra Pusic, M.D., John S. Welch, M.D., Ph.D., Geoffrey L. Uy, M.D., Daniel C. Link, M.D., John F. DiPersio, M.D., Ph.D., Peter Westervelt, M.D., Ph.D., Timothy J. Ley, M.D., Kathryn Trinkaus, Ph.D., Timothy A. Graubert, M.D., and Matthew J. Walter, M.D., Mutation Clearance after Transplantation for Myelodysplastic Syndrome, New England Journal of Medicine 2018, Sep 13, 2018, doi: 10.1056/NEJMoa1804714
Meagan A. Jacoby, Eric J. Duncavage, Gue Su Chang, Christopher A. Miller, Jin Shao Kevin Elliott, Joshua Robinson, Robert S. Fulton, Catrina C. Fronick, Michelle O’Laughlin, Sharon E. Heath, Iskra Pusic, John S. Welch, Daniel C. Link, John F. DiPersio, Peter Westervelt, Timothy J. Ley, Timothy A. Graubert, and Matthew J. Walter, Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant, JCI Insight 2018, Mar 8;3(5). pii: 98962, doi: 10.1172/jci.insight.98962