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Research

 

The Melnick Lab's Research is focused on hacking the immune system’s software control systems to understand lymphomagenesis and create curative immunotherapies

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. 

Essential to this effort is comparing and contrasting lymphomas with the normal immune system, with a special focus on germinal center biology. In recent work we have provided fundamental insights into how B-cells manage to undergo profound and dynamic phenotypic transitions during the humoral immune response through massive changes in their 3D genomic topology, chromatin modification patterns and transcriptional programming.   We have shown how these epigenetic programs shape the immune synapse through which B-cells interact with and influence the function of T-cells and immune stromal elements, and how lymphoma mutations alter the immune synapse to generate a tumor promoting niche.   For example, we have defined at the mechanistic level:

- The precise manner in which the germinal center master regulatory transcription factor BCL6 controls gene promoters and enhancers through formation of distinct regulatory complex (refs),
- The manner in which the PRC1 and PRC2 polycomb complexes are required for and drive the germinal center reaction (refs)
- How mutations in the histone and DNA modifying enzymes EZH2, CREBBP, KMT2D, TET2 and others (refs)
- How disruption of the 3D architectural organization of the B-cell genome leads to malignant transformation and is required to maintain the malignant phenotype of these cells

Current projects in the lab explore the pathogenesis of follicular lymphoma, GC-DLBCL, ABC-DLBCL and marginal zone lymphomas, using genetic approaches that reflect the proper timing and combinations of mutations as they occur in humans, using both murine and primary human systems.  These include the study of epigenetic, topological, and transcription factor associated mechanisms.

 

 
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.   There are many barriers towards development of effective epigenetic therapies, which include:  i) lack of knowledge of how epigenetic mechanisms work, ii) the fact that the epigenome is multilayered so that targeting single targets is unlikely to yield profound effect, iii) the lack of specific and potent therapeutic agents with adequate pharmacokinetic and pharmacodynamic properties, iv) lack of knowledge of how such agents could affect the immune system functions needed to attack tumors, v) lack of understanding the kinetics and timing required for epigenetic therapies to mediate their anti-tumor actions.  

 We advocate for and focus our efforts on development of true “Precision Epigenetic Therapy”, which can be defined as

- Hitting a well-defined and specific epigenetic target
- The target is mainly an epigenetic modifier in the lymphoma context.
- The target drives a defined epigenetic dependency in B-NHL
- Patients can be selected based on biomarkers (e.g. somatic mutations) that indicate dependency on specific epigenetic mechanism

In this view, drugs such as HDAC inhibitors, which affect lysine acetylation of thousands of proteins and have never been demonstrated to mediate their effects through effects on the epigenome would not be considered as a viable therapeutic approach, where as compounds such as EZH2 specific inhibitors are more promising although the manner in which they are delivered and combined requires rigorous scientific research.

Our work examines how epigenetic therapies affect lymphomas with defined genetic backgrounds, as well as the immune system and microenvironment where these tumors reside.   We also use CRISPR screens to help define such targets and  understand mechanisms that enhance or induce resistance. 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 wee 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.

Most AMLs remain incurable and we are especially interested in translating epigenetic therapy for use in AML patients in a manner that will truly benefit these patients.  Our approach involves the intensive use of  genetically defined primary human AML specimens, using tissue organoid and in vivo platforms.   Methods used to understand these mechanisms include genome wide architectural studies such as Hi-ChIP, Cut&tag, Pro-seq, etc, as well single cell omics approaches for transcriptional and epigenetic marks to define drug sensitive cell populations. 

 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.  

 

 

 

Germinal Center B cells using Confocal Microscopy

Cell fate decisions in the germinal center (GC) and derived lymphomas.

Weill Cornell Medicine Melnick Lab 413 E 69th Street, Belfer Building, BB-1462 New York, NY 10021 Phone: 646-962-6726 Fax: 646-962-6729