The Melnick Lab's research is focused on hacking the immune system’s software control systems to understand lymphomagenesis and create curative immunotherapies. Major areas of research include:
How somatic mutations in chromatin modifying proteins induce malignant transformation of the immune system.
We use highly complex genetically engineered mice, cutting edge epigenomic and single cell analysis systems, as well as advanced imaging methods to define with unprecedented depth the biochemical and biological mechanisms through which lymphoma founder mutations reprogram the immune system to support malignant transformation of B-cells. This research involves close collaboration with tissue organoid engineers, microscopy physicists, computational biologists, immunopathologists, and many others, for a truly multidisciplinary and impactful approach towards understanding these immune neoplasms.
How to create targeted epigenetic therapies that eliminate lymphomas by restoring anti-tumor immunity and enhance the activity of immunotherapy agents.
We aim to create and translate true precision epigenetic therapy regimens that will provide definitive solutions for reprogramming the immune the system to reject and eradicate lymphomas. We are especially focused on the rational use of these compounds to enhance the activity of immunotherapy agents such as checkpoint inhibitors, CAR-T cells, etc. Current immunotherapy research largely ignores how specific tumor mutations determine resistance to such treatments, and how those mutations can be targeted to maximize response. Along these lines we aim to create precision epigenetic/immunotherapy pairings that take all of these factors into account so as to create truly curative regimens. Critical to the success of such efforts is our integrated use of syngeneic lymphoma systems such as genetically engineered mice, as well as humanized mice bearing human lymphomas, and clinical trials in canine lymphoma patients. We are currently partnering with Pharma or developing in our own compounds towards this end.
Understanding the epigenetic basis of acute myeloid leukemias and development of combinatorial epigenetic therapies that can eradicate leukemia repopulating cells.
Research from our group established that deregulation of epigenetic mechanisms is the biological hallmark of acute myeloid leukemia (AML). We performed the first genome wide epigenetic profiling studies of these tumors, identified many novel epigenetic disease driving mechanisms such as the example of how IDH mutations and TET2 mutations reprogram the epigenome. We discovered epigenetic allele diversity as a critical mechanism driving development and relapse of AML (as well as lymphomas), and have demonstrated how somatic mutations in epigenetic modifiers such as TET2 result in unexpected reprogramming of the 3D architecture and chromatin landscape of leukemia cells. Current projects in the lab are studying how particular genetic mutations in AML (e.g. NPM1, DNMT3A, TET2, etc.) result in synthetic lethality and vulnerability to particular combinations of epigenetic targeted therapies. | Melnick Lab