# Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $377,055

## Abstract

RESEARCH SUMMARY
 Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common
forms of mature B-cell lymphoma, together accounting for over 70% of all diagnoses. Both diseases remain a
significant clinical challenge, as a significant patient population does not achieve durable remissions following
conventional therapeutic strategies. The identification of molecular mechanisms that are responsible for tumor
initiation and maintenance, and could be vulnerable to targeted therapeutic intervention, represents a research
imperative in order to advance our ability to cure these diseases.
 Somatic mutations leading to inactivation of the KMT2D methyltransferase emerged as the most common
genetic lesion in FL (80% of cases) and DLBCL (~30% of cases), suggesting a prominent role for epigenetic
perturbations in the pathogenesis of these cancers (Pasqualucci et al., Nature Genetics 2011; Morin et al.,
Nature 2011). Indeed, conditional inactivation of KMT2D in vivo leads to the expansion of germinal center (GC)
B cells, the normal counterpart of FL and DLBCL, and cooperates with BCL2 deregulation to increase the
incidence of tumors recapitulating phenotypic and genetic features of the human FL/DLBCL, thereby
establishing KMT2D as a bona fide tumor suppressor gene (Zhang et al., Nature Medicine 2015; Ortega-
Molina et al., Nature Medicine 2015). However, GC-specific deletion of KMT2D individually was insufficient to
drive tumor formation, suggesting the requirement of additional cooperating events. We observed that KMT2D
mutations are frequently associated with alterations in the CREBBP/EP300 acetyltransferases, found in 60% of
KMT2D-mutated FL and ~25% of KMT2D-mutated de novo DLBCL. Both alterations represent early lesions in
lymphomagensis (Pasqualucci et al, Cell Reports 2014). Moreover, CREBBP acetylates the KMT2D protein in
vivo; finally, the chromatin-binding pattern of these two proteins significantly overlaps at GC-specific super-
enhancers (Zhang et al., Nature Medicine 2015 and Cancer Discovery 2017). These data suggest that KMT2D
and CREBBP cooperate in B cell lymphomagenesis by coordinately regulating common and specific programs.
 Building on these results, the general goal of this project will be to elucidate the cooperative role of
KMT2D and CREBBP in normal and transformed GC B cells, with three Specific Aims: i) identify the
transcriptional program coordinately or combinatorially regulated by these two proteins in normal GC B cells,
and disrupted in B cell lymphomas with concurrent inactivating mutations, and the role of CREBBP-mediated
acetylation on KMT2D function; ii) investigate the role of KMT2D/CREBBP enhancer binding in favoring
chromosomal translocations and aberrant somatic hypermutation; and iii) examine the synergistic role of
combined KMT2D/CREBBP deficiency in lymphoma initiation in vivo. We anticipate that the results obtained
from these studies will impact our current understanding of the p...

## Key facts

- **NIH application ID:** 10432012
- **Project number:** 5R01CA172492-10
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Laura Pasqualucci
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,055
- **Award type:** 5
- **Project period:** 2013-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432012

## Citation

> US National Institutes of Health, RePORTER application 10432012, Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma (5R01CA172492-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10432012. Licensed CC0.

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