# Targeting Epigenetic Circuits in B-Cell Lymphomas

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $1,128,045

## Abstract

ABSTRACT
The principal investigator is a physician scientist who has contributed significant discoveries to the cancer
epigenetics field. He has published > 220 scientific papers, 130 of them in the past five years - many of them in
high profile journals, and 30 of which were cited by the Faculty of 1000. He has been continuously NCI funded
since completing his clinical training in 1997. His proposal will elucidate how B-cell lymphomas arise through
disruption of an intricate network of epigenetic mechanisms that regulate and control the humoral immune
response. In the generally accepted model for malignant transformation, somatic mutations cause normal cells
to manifest aberrant phenotypic hallmarks that define them as malignant tumor cells. However, the PI proposes
that malignant transformation occurs in a fundamentally different way in the germinal center (GC) B-cells that
give rise to follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Specifically, he notes that
upon their activation, GC B-cells surprisingly manifest many canonical cancer phenotypes (e.g. massive
proliferation, tolerating genomic instability, etc.), which enables them to undergo rapid clonal evolution and
immunoglobulin affinity maturation. Strikingly the GC reaction is a transient process after which B-cells
extinguish this “pseudo-malignant” phenotype and undergo terminal differentiation, which highlights the PIs
critical point that cancer phenotypes are not inherently irreversible. He proposes the novel hypothesis that FLs
and DLBCLs arise from a failure of the GC B-cell phenotype to resolve due to disruption in the dynamic
equilibrium between histone readers and writers. More specifically, he proposes that the immune synapse
between T-follicular helper and GC B-cells normally signals to the epigenome to re-instate the B-cell
differentiation program that is epigenetically silenced while B-cells undergo the GC reaction. He hypothesizes
that the immune synapse fails to erase GC epigenetic marks and restore B-cell epigenetic marks in the presence
of somatic mutations of the histone acetyltransferases CREBBP and EP300, and histone methyltransferases
KMT2D and EZH2, which occur early during pathogenesis in ~80% of FL and DLBCL patients suggesting that
lymphomas in essence represent uncontrolled GC reactions. Finally he predicts that FLs and DLBCLs with these
mutations can be selectively treated using epigenetic-targeted drugs that counteract the effect of these mutations
on the epigenome. This latter notion is supported for example by his finding that CREBBP mutant lymphomas
are specifically biologically dependent on HDAC3, and that HDAC3 inhibitors reverse the epigenetic,
transcriptional and biological effects of CREBBP mutation. For this research he has assembled unique and novel
technologies such as GC organoids that allow precise, temporal observation of immune synapse signaling, the
necessary genetically engineered mouse models, and extensive libraries of...

## Key facts

- **NIH application ID:** 9999451
- **Project number:** 5R35CA220499-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** ARI M. MELNICK
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,128,045
- **Award type:** 5
- **Project period:** 2018-09-13 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999451

## Citation

> US National Institutes of Health, RePORTER application 9999451, Targeting Epigenetic Circuits in B-Cell Lymphomas (5R35CA220499-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999451. Licensed CC0.

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