# Epigenetic basis and therapeutic targeting of the unique lymphoma immunological niche

> **NIH NIH P01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $2,561,215

## Abstract

OVERALL: ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is an aggressiveand clinically heterogeneous malignancy derived from
B-cells transiting the germinal center (GC) reaction. Indeed, the biological heterogeneity of DLBCL aligns with a
continuum of developmental states within and subsequent to the GC reaction. The genetic hallmarks of DLBCL
are somatic mutation in chromatin modifier and transcription factor genes and immune synapse signaling
mediators. Examining mechanisms of action for these mutations has provided insights into discrete cell-intrinsic
processes that are deregulated in DLBCL, but do not account for how these mutations function, when they occur
together in the same lymphoma cells, how they shape the lymphoma microenvironment LME, how the LME
influences lymphomas, and how critical host features such as age influence and define the nature of these
lymphomas and their LME. DLBCLs are thus complex entities from the systems biology and immunological
standpoint and a paradigm shift in our thinking about these tumors is necessary to arrive at a definitive
understanding of disease pathogenesis and effective and precise therapeutic strategies. To address this
challenge we have assembled a team of experts with distinct spheres of expertise, suites of cutting edge
technologies and powerful and physiologically accurate model systems. They have worked together as a team
to develop a compelling body of preliminary data supporting the conceptual framework of this proposal, and have
developed critical resources such as shared genomics databases, primaryhuman PDX repositories, genetically
engineered mouse models, computational pipelines and graphical user interfaces, and others. They will address
the central hypotheses that i) chromatin is the key integrator, rheostat and executor of cell-intrinsic and cell-
extrinsic pathways regulating key GC cell fate decisions downstream of immune synapse signaling, ii) DLBCLs
reflect a continuum of malignant states with each tumor aligning with one or more points along GC B-cell
epigenetic trajectories, iii) GCB and ABC DLBCLs are defined by crosstalk between their chromatin landscapes
and other immune populations to shape the LME, iv) that these chromatin to LME effects vary in specific ways
with mutation profiles and with aging age, and that v) rational targeting of DLBCLs must take into account and
specifically antagonize these specific chromatin-immune synapse - LME scenarios to achieve long term tumor
eradication.

## Key facts

- **NIH application ID:** 10847986
- **Project number:** 1P01CA272295-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Leandro C Cerchietti
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,561,215
- **Award type:** 1
- **Project period:** 2024-08-12 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847986

## Citation

> US National Institutes of Health, RePORTER application 10847986, Epigenetic basis and therapeutic targeting of the unique lymphoma immunological niche (1P01CA272295-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10847986. Licensed CC0.

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