# Protection of stressed hematopoietic stem cells by the tetraspanin family member CD53

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $388,750

## Abstract

Project Summary/Abstract
The goal of this proposal is to understand how the tetraspanin family member CD53 protects hematopoietic stem
cells (HSCs) from inflammatory stress. While important for normal immune system function, inflammatory
signaling can impair HSC function and promote the development of hematopoietic malignancies. In preliminary
data, we identified CD53 as a critical regulator of HSC function in the context of inflammatory stress. CD53 is a
member of the tetraspanin family of transmembrane proteins that organize multi-protein networks to regulate a
wide variety of cellular processes such as proliferation, migration, and survival. While normally expressed at very
low levels in HSCs, CD53 is markedly upregulated in response to multiple stressors including inflammatory
cytokines, toll like receptor agonists and mobilizing agents. Using our newly-generated Cd53-/- mouse, we found
that loss of CD53 causes a significant reduction in HSC repopulating ability and increased cycling in the face of
inflammatory stress. RNA sequencing and proximity labeling studies suggest that CD53 promotes HSC
quiescence in response to inflammation via activation of “DREAM,” a transcriptional repressor complex involving
the Rb-like family members p107/Rbl1 and p130/Rbl2 that inhibits the expression of cell cycle genes in response
to p53 and p21 activation. Based on this data, we hypothesize that CD53 promotes DREAM complex-mediated
repression of cell cycle-related genes in HSCs in response to inflammatory stress, thereby promoting HSC
quiescence and protecting HSC function. Notably, CD53 expression is markedly increased in HSCs deficient for
Tet2 or Dnmt3a. Mutations in these epigenome regulators are commonly associated with age-related clonal
hematopoiesis (CH), which involves inflammation-driven expansion of mutant HSCs and increased risk of
leukemic transformation. We predict that CD53 may thus promote the clonal advantage of mutant HSCs in CH.
Using a combination of proteomic, transcriptomic and in vivo HSC functional tools, we will: 1) Determine the role
of CD53 in promoting HSC function in response to inflammatory stimuli; 2) Determine how CD53 regulates HSC
cycling and DREAM complex activity; and 3) Determine whether elevated CD53 promotes the clonal advantage
of mutant HSCs. We will perform overexpression studies to elucidate the effects of sustained CD53 expression
on HSC function, and DREAM knockout mice will be used to determine the role of this complex in mediating the
effects of CD53 on HSCs. We will determine the mechanisms by which CD53 regulates HSC cycling and DREAM
activation using proximity ligation assays to characterize CD53- interacting partners. Finally, we will perform
functional studies and chimeric modeling experiments using Cd53 and Dnmt3a knockout mice to determine
whether CD53 promotes the clonal expansion of mutant HSCs. Together, our proposed studies will describe a
novel mechanism that enables HSCs to resist inflammatory stres...

## Key facts

- **NIH application ID:** 10754950
- **Project number:** 5R01HL134896-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** LAURA G. SCHUETTPELZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2017-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754950

## Citation

> US National Institutes of Health, RePORTER application 10754950, Protection of stressed hematopoietic stem cells by the tetraspanin family member CD53 (5R01HL134896-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10754950. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*