# ROLE OF TLR2 IN REGULATING NORMAL AND PREMALIGNANT HEMATOPOIETIC STEM CELLS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $381,250

## Abstract

PROJECT SUMMARY
 The goal of this project is to understand how inflammatory signaling through toll like receptor 2 (TLR2)
regulates both normal and premalignant hematopoietic stem cells (HSCs). TLR2 is a member of the TLR family
of pattern-recognition receptors that play a central role in the innate immune response. Studies of TLRs have
largely focused on mature immune cell populations, however TLRs are also expressed on HSCs, and recent
reports demonstrate that TLR signaling may influence the immune response from the level of the HSC.
Furthermore, deregulated TLR signaling, and in particular increased TLR2 expression and signaling, is
associated with myelodysplastic syndromes (MDS), a group of HSC disorders characterized by ineffective
hematopoiesis and a high risk of transformation to acute leukemia. Thus, aberrant TLR2 signaling may have
clinically significant detrimental effects on HSCs.
 Our preliminary data suggest that TLR2 signals influence HSC numbers, mobilization and function.
Using chimeric mouse studies, we determined that these effects of TLR2 signaling on HSCs are mediated by
both cell autonomous and cell non-autonomous mechanisms. We therefore hypothesize that TLR2 signaling
from multiple cell types contributes to the regulation of HSCs, and TLR2-induced changes in HSC function may
contribute to the pathogenesis of MDS. In this proposal we will use CyTOF mass cytometry and conditional
knockout mouse studies to identify the cell types in which TLR2 signaling is enhanced in MDS and determine
the effects of conditional loss of TLR2 signaling from different hematopoietic and stromal cells types to the
regulation of HSCs. In addition, we will use a mouse model of MDS in which we either augment or reduce
TLR2 signaling to test the hypothesis that enhanced TLR2 signaling contributes to the pathogenesis of this
disease. These studies will further our understanding of how TLR2 regulates HSCs and test it's utility as a
therapeutic target in MDS. More broadly, we hope to gain a better understanding of how TLR signals regulate
both normal and premalignant HSCs, and we anticipate that these studies will have implications not only for
the pathogenesis of MDS, but for how aberrant TLR signaling (e.g., chronic infection) may contribute to other
cases of bone marrow failure and/or leukemogenesis. Future studies will build upon these results and focus on
the downstream mediators of the effects of TLR2 signaling on HSCs, with the goal of identifying genes that
contribute to HSC cycling, differentiation, mobilization and/or loss of function in response to TLR signals.

## Key facts

- **NIH application ID:** 10073537
- **Project number:** 5R01HL134896-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** LAURA G. SCHUETTPELZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073537

## Citation

> US National Institutes of Health, RePORTER application 10073537, ROLE OF TLR2 IN REGULATING NORMAL AND PREMALIGNANT HEMATOPOIETIC STEM CELLS (5R01HL134896-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073537. Licensed CC0.

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