David Langenau, PhD
Assistant Professor, Department of Pathology, Harvard Medical School
Assistant Molecular Pathologist, Molecular Pathology, Massachusetts General Hospital
DF/HCC Program AffiliationLeukemia
Lab WebsiteDr. Langenau Harvard Stem Cell Institute ProfileLangenaulabDr. Langenau MGH Cancer Center Profile
The Langenau laboratory research focus is to uncover relapse mechanisms that alter growth, therapy resistance, and tumor propagating cell frequency in pediatric cancer. Utilizing zebrafish models of T-cell acute lymphoblastic leukemia (T-ALL) and embryonal rhabdomysoarcoma (ERMS), we have undertaken chemical and genetic approaches to identify novel modulators of growth and relapse. One research project focused on uncovering progression-associated driver mutations in T-cell acute lymphoblastic leukemia. T-ALL is an aggressive malignancy of thymocytes that affects thousands of children and adults in the United States each year. Recent advancements in conventional chemotherapies have improved the five-year survival rate of patients with T-ALL. However, patients with relapse disease are largely unresponsive to additional therapy and have a very poor prognosis. Ultimately, 70% of children and 92% of adults will die of relapse T-ALL, underscoring the clinical imperative for identifying the molecular mechanisms that cause leukemia cells to re-emerge at relapse. Utilizing a novel zebrafish model of relapse T-ALL, large-scale trangenesis platforms, and unbiased bioinformatic approaches, we have uncovered new oncogenic drivers associated with aggression, therapy resistance and relapse. A large subset of these genes exert important roles in regulating human T-ALL proliferation, apoptosis and response to therapy. Discovering novel relapse-driving oncogenic pathways will likely identify new drug targets for the treatment of T-ALL. The second major research focus of our group is to visualize and kill cancer stem cells in embryonal rhabdomyosarcoma. ERMS is a common soft-tissue sarcoma of childhood and phenotypically recapitulates fetal muscle development arrested at early stages of differentiation. Microarray and cross-species comparisons of zebrafish, mouse and human ERMS uncovered the finding that the RAS pathway is activated in a majority of ERMS. Building on this discovery, our laboratory has developed a transgenic zebrafish model of kRASG12D-induced ERMS that mimics the molecular underpinnings of human ERMS. We used fluorescent transgenic zebrafish that label ERMS cell subpopulations based on myogenic factor expression, to identify functionally distinct classes of tumor cells contained within the ERMS mass. Specifically, the myf5-GFP+ self-renewing cancer stem cell drives continued tumor growth at relapse and is molecularly similar to a nontransformed, activated muscle satellite cell. Building on the dynamic live cell imaging approaches available in the zebrafish ERMS model, our laboratory has undertaken chemical genetic approaches to identify drugs that kill relapse-associated, self-renewing myf5-GFP+ ERMS cells. We are currently assessing a subset of drugs for their ability to regulate growth of human ERMS cells.
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