# Roles of Coactivator-Associated Arginine Methyltransferase 1 in B cell activation and lymphomagenesis

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $444,382

## Abstract

PROJECT SUMMARY
 Follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are the most common germinal center
(GC)- derived Non-Hodgkin B cell lymphomas (BCLs). Although initially exhibiting an indolent behavior, FLs end
up being mostly incurable with 40-50% eventually transforming into an aggressive and lethal form of DLBCL.
Although half of DLBCLs can be cured with standard chemotherapy and immunotherapy, many patients are still
refractory and succumb to progressive or relapsed disease. In addition, the strong chemotherapy regimens used,
even when tolerated, have deleterious side and late effects. Thus, less toxic, targeted therapies are in urgent
need for this disease. Recent advances in the molecular biology of DLBCL uncovered critical pathways in the
initiation and development of these neoplasms. Of particular importance are next-generation sequencing studies
that identified mutations in epigenetic modifiers that led to the development of current active clinical trials using
epigenetic therapies in DLBC. Among their highest recurrent disease alleles are somatic mutations affecting two
closely related histone acetyltransferase (HAT) genes, Crebbp and EP300. These are frequently monoallelic,
within the HAT domain and usually mutually exclusive, suggesting that they 1) might affect a common pathway
and 2) residual WT expression of CREBBP and/or EP300 is required for cell survival. We have identified the
protein arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase1) as an important
factor to maintain the survival of CREBBP/EP300 mutated BCLs. A potent effective small molecule inhibitor of
CARM1 methylation activity has been recently developed and we hypothesize that targeting CARM1 methylation
activity in CREBBP/EP300 mutated BCLs causes synthetic lethality. The major goals of this proposal are to
determine how inhibition of CARM1 methylation activity affects BCLs harboring CREBBP/EP300 genetic lesions
and define the molecular mechanism responsible for the sensitivity of CREBBP/EP300 BCLs to CARM1
inhibition. We anticipate that the results obtained from these studies will impact our current understanding of the
pathogenesis of GC-derived BCLs, by providing new insights on the mechanisms of neoplastic transformation.
Altogether we ultimately expect that these results will make a strong rationale for future clinical studies using
CARM1 inhibitors in Crebbp/Ep300 mutated BCLs.

## Key facts

- **NIH application ID:** 10361507
- **Project number:** 5R01CA247883-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael Richard Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,382
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10361507

## Citation

> US National Institutes of Health, RePORTER application 10361507, Roles of Coactivator-Associated Arginine Methyltransferase 1 in B cell activation and lymphomagenesis (5R01CA247883-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10361507. Licensed CC0.

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