# Mechanisms of epitranscriptomic regulation in cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $623,304

## Abstract

SUMMARY N6-methyladenosine (m6A) is a modified nucleotide in mRNA whose transcriptome-wide
expression and distribution are altered in various cancers, including acute myeloid leukemia (AML) cells. m6A
has a pivotal role in controlling cell fate decisions especially in the hematopoietic lineage. Our recent work has
revealed that this effect of m6A is mediated in part by its ability to regulate “symmetric commitment,” in which a
stem cell differentiates into two daughter cells that both adopt the same new cell identity. We recently
identified SON, one of the most highly methylated transcripts in hematopoietic stem cells, as a major mediator
of m6A-dependent control of symmetric commitment. However, the mechanism by which SON regulates these
phenomena is unclear, and moreover it is unclear if deregulated m6A control over SON contributes to the
undifferentiated phenotype of AML cells. Inhibitors of METTL3, the m6A biosynthetic enzyme, are a promising
approach to target AML, but appear to exhibit diverse effects in cells not seen with METTL3 knockout. Also,
unlike METTL3 knockout, METTL3 inhibitors also appear to preferentially target cancer cells. A major goal is
to understand the basis for the actions of METTL3 inhibitors compared to METTL3 knockout and to determine
if specific cellular pathways can influence whether cells, and ultimately patients, would be more or less
sensitive to METTL3 inhibitor treatment. To significantly advance our understanding of epitranscriptomic
regulation in cancer, the specific aims of this proposal are: (1) To define the functional requirement for SON
and nuclear RNA methylation on cell fate in leukemia. In this aim we will use a new conditional knockout
mouse model to dissect SON's stage-specific role, clarifying its impact on METTL3-related blood phenotypes.
We will determine SON's importance in leukemia and unravel its downstream targets, mRNA regulatory
mechanisms, and links to the RNA methylation. (2) To identify pathways and mechanisms that make
cancer cells sensitive to METTL3 inhibition. Our preliminary data show that METTL3 inhibitors cause
marked reorganization of nuclear architecture, and their effects can be overcome by forced expression of
YTHDC1. We have also identified additional suppressors of METTL3 inhibitors by performing a base editor
screen to generate >600 oncogenic mutations and probing how the mutations affect sensitivity to METTL3
inhibitors. We will broadly identify how YTHDC1 and these newly discovered oncogenic pathways influence
the m6A pathway and METTL3 inhibitors. (3) To determine the function of m66A in MYC mRNA. Our
studies revealed the presence of a previously unidentified epitranscriptomic mark, N6,N6-dimethyladenosine
(m6,6A) as a highly prevalent evolutionarily conserved modification in MYC mRNA. We will determine the
prevalence and functional significance of this new modification, and determine how it impacts the oncogenic
function of MYC. Overall, this project develops new techno...

## Key facts

- **NIH application ID:** 10990904
- **Project number:** 2R01CA186702-11
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** SAMIE R JAFFREY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,304
- **Award type:** 2
- **Project period:** 2014-09-10 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990904

## Citation

> US National Institutes of Health, RePORTER application 10990904, Mechanisms of epitranscriptomic regulation in cancer (2R01CA186702-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10990904. Licensed CC0.

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