# From pathogenesis to new therapeutic targets in diffuse large B cell lymphoma

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $937,650

## Abstract

PROJECT SUMMARY
Diffuse Large B cell Lymphoma (DLBCL) is incurable in ~30% of patients and, despite recent advances in CAR-
T cell therapies, remains a significant clinical challenge. One barrier to rationally targeted new therapies is the
remarkable heterogeneity of these tumors, which leaves as many as 20-50% of cases unclassified based on
cell-of-origin or more recent genetic-based classifications. This may be due in part to the fact that current
taxonomies are limited to the analysis of coding regions, representing only 3% of the genome, while further
genetic complexity of pathogenetic relevance may reside in the non-coding regulatory portion of the genome. To
this end, we recently investigated whether critical regulatory domains such as enhancers and super-enhancers
(SEs) could be the site of functionally relevant mutations in DLBCL. We found that regions corresponding to
active SEs are highly and specifically hypermutated in 97% of DLBCL cases, as compared to the same loci when
not active as SE. Such aberrant SE hypermutation displays signatures of AID activity and is linked to genes
encoding B cell regulators and well-established oncogenes. As evidence of oncogenic relevance, we showed
that the hypermutated SEs linked to the BCL6, BCL2, and CXCR4 proto-oncogenes prevent the binding and
transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1
(BCL6) and the steroid-receptor NR3C1 (BCL2 and CXCR4). Of note, CRISPR/Cas9-mediated correction of the
SE hotspot mutation restored target gene regulation and impaired cell growth, indicating a key role for the SE
mutation in maintaining the transformed phenotype (Bal et al., Nature 2022). Overall, these findings identify a
highly pervasive, pathogenetically relevant, mutational mechanism that is likely to significantly influence the
current understanding of the somatic genetic landscape of DLBCL. The overall goal of this research program will
be to: i) identify and mechanistically dissect the top recurrently mutated/functionally relevant SEs and associated
target genes; ii) understand the role of the glucocorticoid receptor pathway, which appears to be commonly
targeted by the SE hypermutation mechanism as well as by direct coding mutations, in normal B cell biology and
lymphomagenesis. We anticipate that this new layer of genetic alterations will identify novel mechanisms of
dysregulation for known oncogenes, as well as new dysregulated genes and pathways, with implications for
precision classification and therapeutic targeting of DLBCL.

## Key facts

- **NIH application ID:** 10928175
- **Project number:** 5R35CA210105-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Riccardo Dalla-Favera
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $937,650
- **Award type:** 5
- **Project period:** 2023-09-12 → 2030-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928175

## Citation

> US National Institutes of Health, RePORTER application 10928175, From pathogenesis to new therapeutic targets in diffuse large B cell lymphoma (5R35CA210105-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10928175. Licensed CC0.

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