# The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2021 · $99,999

## Abstract

Abstract
Myelodysplastic syndromes (MDS) are a group of diverse malignant hematological disorders that originate
from hematopoietic stem cells (HSCs). Increased levels of reactive oxygen species (ROS) and DNA damage
were detected in hematopoietic cells from MDS patients. An elevated level of ROS that can be generated from
both endogenous and exogenous sources as well as oncogene activation, leads to loss of quiescence and
self-renewal of HSCs. ROS-induced DNA damage speeds up aging process of stem cells and contributes to
the mutagenesis associated with cancer development. m6A RNA methylation has significant roles in multiple
biological processes by introducing another layer of post-transcriptional regulation of gene expression within
cells. The goal of this project is to elucidate the role of crosstalk between RNA epigenetic regulation and DNA
damage repair in the maintenance of genomic stability in hematopoietic stem/progenitor cell (HSPCs) during
oxidative stress, and how deregulation of ALKBH5 contributes to promotion of leukemic transformation of
HSPCs in the initiation and development of MDS. We found that ROS significantly increased global m6A RNA
methylation in human cell lines, and that the elevation of m6A mRNA methylation is required for rapidly
repairing ROS-induced DNA lesions and preventing cell death. Interestingly, we found that ALKBH5, the m6A
RNA demethylase, is responsible for ROS-induced elevation of m6A mRNA methylation. ROS induced post-
translational modification of ALKBH5, and inhibited the demethylase activity of ALKBH5. We showed that
forced expression of ALKBH5 inhibited ROS-induced m6A mRNA methylation and significantly delayed repair
of ROS-induced DNA damage. Thus, we hypothesize 1) that ALKBH5-mediated m6A modification has a
significant role in the maintenance of genome integrity and survival of cells in response to oxidative stress in
HSPCs; and 2) that deregulation of ALKBH5 may disrupt HSPC functions, thereby promoting leukemic
transformation of HSPCs. In this proposal, we will determine 1) the role and underlying mechanism of Alkbh5
in the maintenance of genomic stability in HSPCs in response to oxidative stress; 2) the role of
ALKBH5/Alkbh5 in the maintenance of mouse and human primary HSPCs during ROS stress in vivo; and 3)
how ALKBH5/Alkbh5 contributes to the development of del(5q) MDS. We will employ both genetic murine
models as well as patient-derived xeno-transplantation (PDX) models to investigate the role of ALKBH5 in the
maintenance of HSPCs in vivo, and will combine transcriptome and epitranscriptome analysis to identify the
key downstream targets and associated downstream pathways that mediate the role of ALKBH5 in HSPCs
with or without ROS-induced stress. Our study will provide new insights into novel mechanisms underlying
epitranscriptional regulation of gene expression as well as uncover novel mechanisms that regulate the activity
of ALKBH5 in response to oxidative stress. This study will provide ...

## Key facts

- **NIH application ID:** 10476005
- **Project number:** 1R56DK129489-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Zhijian Qian
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $99,999
- **Award type:** 1
- **Project period:** 2021-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476005

## Citation

> US National Institutes of Health, RePORTER application 10476005, The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs (1R56DK129489-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10476005. Licensed CC0.

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