# Mechanisms and functions of N6-methyladenosine (m6A) in cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $550,845

## Abstract

SUMMARY
An important mechanism of gene expression regulation is dynamically regulated, and possibly reversible,
nucleotide modifications in mRNA. These modifications can have marked effects on mRNA stability,
translation, and other aspects of mRNA metabolism. We had a founding role in this field by developing the
technology for transcriptome-wide mapping of N6-methyladenosine (m6A). Our mapping study provided the
first evidence that m6A could be dynamically regulated, and potentially impart new functions in mRNA. We
recently showed that acute myeloid leukemia (AML) cells exhibit elevated levels of METTL3 and METTL14, the
heterodimer that acts as the m6A-forming methyltransferase. We found that m6A promotes self-renewal in
AML and in CD34+ stem cells, and depletion of m6A triggers a differentiation program. Thus, m6A has critical
roles in hematopoietic differentiation at specific stages of development, and this process is deregulated in
AML. Therefore, precise characterization of these stage-specific patterns of m6A at a transcriptome-wide level
is critical to understand how m6A affects developmental transitions. Developing new methods to map m6A in
the rare cell populations relevant to hematopoiesis and AML would help to reveal how this epitranscriptomic
modification is critical for the regulation and deregulation of differentiation seen in AML, and possibly other
cancers. Additionally, the effects of m6A are largely thought to reflect the actions of specific “reader” proteins,
which bind m6A in mRNA to affect its fate in cells. The major readers are YTHDC1 in the nucleus, and the
YTHDF family in the cytoplasm, which comprise three nearly identical paralogs, and which may have
redundant functions. In order to significantly advance our understanding of the role of m6A in AML, the
specific aims of this proposal are: (1) To visualize and map m6A in mRNA in a cell-type specific manner.
Here we describe the development of methods for detecting and mapping m6A in a cell type-specific manner
and their application to understand m6A dynamics in hematopoiesis and AML. (2) To define the functional
requirement for the m6A reader YTHDC1 in normal blood cells and in AML. Based on a genome-wide
screen and our preliminary data, YTHDC1 is a strong candidate for the reader that may mediate major aspects
of the effect of m6A in AML. Here we assess the functional role for YTHDC1 in both normal and malignant
hematopoiesis using human cord blood cells, AML cell lines and primary AML patients. (3) To determine the
roles and regulation of the YTHDF cytosolic m6A readers on mRNA fate. The YTHDF proteins appear to
be the major regulators of m6A mRNAs in the cytosol. We will determine how YTHDF proteins are regulated to
mediate their m6A-mRNA destabilizing effects and if YTHDF proteins influence cellular differentiation and
proliferation in cancer cell lines and in AML. Overall, our project will develop new enabling technologies for
studying m6A in cancer and test mechanis...

## Key facts

- **NIH application ID:** 10461908
- **Project number:** 5R01CA186702-09
- **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:** 2022
- **Award amount:** $550,845
- **Award type:** 5
- **Project period:** 2014-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461908

## Citation

> US National Institutes of Health, RePORTER application 10461908, Mechanisms and functions of N6-methyladenosine (m6A) in cancer (5R01CA186702-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10461908. Licensed CC0.

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