# Role of RNA methylation in chemoresistant cancer cells

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $231,860

## Abstract

Summary Role of RNA methylation in chemoresistant cancer cells
Goal Based on our data, we propose that transiently quiescent populations in acute myeloid leukemia (AML)
are maintained in part by RNA methylation, permitting synthesis of survival and tumor promoting regulators
necessary for chemoresistance and subsequent AML persistence. The primary objective is to characterize the
role of RNA methylation in regulating gene expression in resistant AML, which contributes to chemosurvival.
Significance AML is a serious malignancy that displays clinical resistance due to heterogeneity. Resistant
AML cells include quiescent (G0) cells that are transiently arrested states, and thus resist clinical therapy that
targets only cycling cells; these cells re-enter proliferation to cause AML persistence. A primary issue is that
resistance regulators remain to be uncovered. A second need is to identify markers to detect resistant cells.
Such cells show distinct gene expression that permits chemosurvival (PNAS 2014, Mol. Cell 2016, Biorxiv/
418715). Canonical translation is decreased; yet specific mRNAs are expressed by unknown mechanisms.
Regulation of specific gene expression in resistant AML needs to be uncovered & targeted to curtail AML.
Premise Profiling in resistant cells revealed expression of factors that affect cell survival. Expressed mRNAs in
G0 resistant cells have extended 3? untranslated regions (UTRs) to include regulatory sites, such as for RNA
methylation. Methylation at N6 position of adenosines (m6A) are unique marks on RNAs that regulate gene
expression via RNA binding proteins called readers, to control distinct cell states. Role of m6A in resistant AML
remains to be uncovered. We find the m6A methyltransferase increases due to therapy induced signals. Our
data reveal that m6A is needed for specific gene expression & resistance. We developed inhibitors to block
therapy induced signals & antisense to block unique m6A sites on extended 3’UTRs, which reduce resistance.
These data suggest that m6A regulates specific gene expression to enable therapy survival. Characterization
of mRNAs that are modified & expressed in resistant cells, in vivo & in patient samples by m6A, their readers,
their role in resistance, & of inhibitors that block m6A, will provide markers & therapeutics to curb resistance.
Method Aim I will characterize m6A readers that regulate known modified mRNAs, by in vivo crosslinking
coupled RNA affinity purification in resistant AML cells & in vivo models. Chemical inhibitors to therapy induced
signaling that promotes m6A and antisense to block mapped m6A sites will be tested to curb resistance. Aim II
will globally identify m6A targets that contribute to resistance in cell lines & in vivo models, using m6A antibody
& methyltransferase immunoprecipitation. Role of readers & m6A mRNAs in resistant cells & in vivo is tested
by depletions coupled with chemosurvival assays; their expression will be verified in resistant patient sampl...

## Key facts

- **NIH application ID:** 9896260
- **Project number:** 1R21CA220103-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shobha Vasudevan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $231,860
- **Award type:** 1
- **Project period:** 2020-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896260

## Citation

> US National Institutes of Health, RePORTER application 9896260, Role of RNA methylation in chemoresistant cancer cells (1R21CA220103-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896260. Licensed CC0.

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