# Role of novel onco-histone mutations in B-cell malignancies

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $664,854

## Abstract

The genetic information encoded in DNA is packaged and interpreted by the cellular machinery within the
context of chromatin. As the genome sequence remains largely unchanged throughout development,
chromatin modifications represent a critical interface between the genome and regulatory inputs. Histone
proteins are major constituents of chromatin; four core histone types make up the nucleosome particle, the
basic unit of chromatin. The fifth type, linker histone H1, binds the nucleosome and the linker DNA between.
Whereas the progress in understanding the function of core histones is significant in recent years, much of the
linker histone H1 biology remains unknown. Mutations in linker histone H1 have been recently reported in
approximately 30% of follicular lymphomas and diffuse large B cell lymphomas, and we have identified H1
mutations in 85% of Hodgkin's lymphomas of the nodular sclerosis subtype. Based on preliminary data, we
hypothesize that H1
stem
restricted
dependency
clones.
B
occurring
causing
cooperates
overarching
immune
this
control
to
tumor
isoform loss of function induces lymphomagenesis by ectopically inducing an embryonic
cell (ESC) gene expression signature that imparts unlimited self-renewal in GC B-cells that are otherwise
in their ability to proliferate. We propose that ESC gene expression frees B-cells from their
on T-cell help to survive and divide, resulting in expansion of aberrant pre-neoplastic B-cells
Mechanistically, we propose that H1 is involved in PRC2 recruitment and chromatin compaction during
cell differentiation, thereby repressing ESC genes. Thus, loss of function of H1 through somatic mutations
in germinal center B cells results in reduction and redistribution PRC2 and H3K27 methylation
chromatin decompaction and expression of ESC genes. Finally, we predict that H1 loss of function
with lymphoma oncogenes such as BCL2 to induce malignant transformation. The
goa of the proposed research is to reveal the contributions of linker histones to the humoral
response and lymphomagenesis from both biochemical and biological perspectives. We will achieve
through the following specific aims: 1) Determine the role and mechanism through which H1 is required to
 the GC reaction; 2) Determine the mechanism through which H1 mutations reprogram the epigenome
drive lymphomagenesis; and 3) Determine whether and how H1 soforms function as bona fide lymphoma
suppressors. The study of H1 is quite challenging, but we are uniquely poised to unravel
GC
canonical
l
i
the molecular
details and functional consequences of H1mutations in lymphoid carcinogenesis by bringing together leaders
in the field of transcriptional regulation, chromatin, epigenetic regulation and lymphomagenesis.

## Key facts

- **NIH application ID:** 9981709
- **Project number:** 5R01CA234561-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** CHARLES DAVID ALLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $664,854
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981709

## Citation

> US National Institutes of Health, RePORTER application 9981709, Role of novel onco-histone mutations in B-cell malignancies (5R01CA234561-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981709. Licensed CC0.

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