# Elucidating and targeting the effects of oncogenic histone mutations

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $273,839

## Abstract

PROJECT SUMMARY/ABSTRACT
Histone genes are frequently mutated in cancer, but the significance of most histone mutations is unknown and
few strategies to therapeutically target tumors harboring histone mutations have been developed. Histones are
a fundamental component of chromatin, which regulates the accessibility of DNA for gene expression through
dynamically regulated combinatorial post-translational modifications (PTMs) of histones’ N-terminal tails.
Classical oncogenic histone (‘oncohistone’) mutations directly prevent the ‘writing’ of some of these PTMs,
promoting oncogenesis through altered transcription patterns that inhibit differentiation. The PI and his
collaborators have recently characterized an unexpectedly broad landscape of novel oncohistone mutations that
occur in roughly 4% of tumors. The goal of the proposed work is to understand the impact of a subset of these
novel oncohistones on chromatin and tumor biology and to develop strategies to therapeutically target tumors
expressing oncohistones. Preliminary data presented in this proposal show (a) that a class of novel oncohistone
mutations at H3 N-terminal arginine (H3R) residues alter nearby regulatory PTMs and impair cellular
differentiation, and (b) that differentiation blockade driven by the classical H3K36M oncohistone mutation can be
rescued by tyrosine kinase inhibition. Therefore, experiments are proposed to test the hypotheses that H3R
oncohistone mutations disrupt the chromatin landscape, alter transcription, and dysregulate cellular functions,
and that tyrosine kinase signaling mediates oncohistone-induced differentiation blockade. To rigorously test
these hypotheses, experiments are proposed to (1) elucidate the effects of novel oncohistone mutations on the
chromatin landscape and chromatin-dependent transcription, differentiation, and tumorigenesis and (2)
determine how inhibition of kinase signaling rescues classical oncohistone-induced differentiation blockade. The
proposed work will improve understanding of cancer-associated histone mutations and may lead to the
development of new genotype-directed cancer therapies. The PI, a Medical Oncology Fellow at Memorial Sloan
Kettering Cancer Center (MSKCC), has developed a 5-year career development plan that builds upon his
scientific background in chemical biology and clinical training in medical oncology. He will conduct the proposed
research under the mentorship of Dr. C. David Allis, an internationally recognized expert in oncohistone
mutations and epigenetics, and will develop new skills in chromatin biology including chromatin-relevant
bioinformatics and biochemistry that are critical for his future career focused on understanding and
therapeutically targeting epigenetically driven cancers. This training, combined with his background, mentorship,
and the institutional environment of MSKCC and partner institution The Rockefeller University, positions the PI
to successfully transition to independence as an academic ph...

## Key facts

- **NIH application ID:** 10247837
- **Project number:** 5K08CA245212-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Benjamin A Nacev
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $273,839
- **Award type:** 5
- **Project period:** 2019-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247837

## Citation

> US National Institutes of Health, RePORTER application 10247837, Elucidating and targeting the effects of oncogenic histone mutations (5K08CA245212-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247837. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*