# Identifying Inflammatory Mediators of Clonal Hematopoiesis

> **NIH NIH F99** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $25,431

## Abstract

PROJECT SUMMARY/ABSTRACT
Clonal hematopoiesis (CH) is a common phenomenon defined as the presence of somatic mutations in
hematopoietic stem and progenitor cells (HSPCs) and their expansion in the absence of overt hematological
disease. CH-mutant mature, myeloid cells are believed to generate an inflammatory microenvironment
promoting the fitness advantage of mutant HSPCs. These, in turn, would expand at higher rates and differentiate
into more elevated numbers of myeloid cells, thereby establishing a positive feedback loop between inflammatory
signaling and clonal expansion. Yet, whether CH-mutant HSPCs can also trigger cell-autonomous inflammatory
signaling to provide a selective clonal advantage for themselves remains unknown. CH increases the risk of
hematological malignancy, cardiovascular disease, and mortality from solid tumors. Due to these adverse
outcomes and the high prevalence of CH in the elderly, there is an unmet need to develop novel therapies.
Targeting inflammation specifically in mutant HSPCs —to avoid disruption of general immune responses— may
be a potentially effective strategy. My predoctoral research (Aim 1) aims to identify inflammatory mediators of
CH-mutant HSPCs and evaluate their potential as therapeutic targets to restore oligoclonal hematopoiesis. To
find novel, cell-autonomous inflammatory pathways in CH, I have designed an sgRNA library to target
inflammation-associated genes. Using this library for high-throughput CRISPR/Cas9 screening, I have identified
both general and genotype-specific inflammatory dependencies of CH-mutant murine HSPCs. In this proposal,
Specific Aim 1.1 seeks to validate the negative selection hits, demonstrate that, when present, the hit genes
confer a selective advantage to CH-mutant HSPCs versus wild-type counterparts, and delineate the specific role
of credential top hits in clonal expansion. In Specific Aim 1.2, I will use small molecule inhibitors targeting
the candidate genes —both ex vivo and in mice— to identify gene expression and cytokine profile changes
spanning the hematopoietic cell subsets. I will then assess differences between genetic and chemical approaches
concerning their efficiency in achieving adequate target inhibition. My postdoctoral research (Aim 2) will focus
on the role of inflammation at the nexus of aging and CH by uncovering the transcriptional and epigenetic
mechanisms by which age-related inflammation promotes CH and potential malignant transformation to
leukemia. Overall, these two projects, which will use human samples to validate the mouse findings, will lead to
developing new therapies targeting inflammation to halt or revert CH and mitigate its clinical sequelae. I, the
applicant, will conduct this proposal in the laboratory of Dr. Ross Levine at Memorial Sloan Kettering Cancer
Center (MSK), one of the world's leading institutions in cancer treatment and research. MSK's rich environment
and abundant resources in conjunction with the support of the Gerstn...

## Key facts

- **NIH application ID:** 10908648
- **Project number:** 5F99CA284253-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ines Fernandez Maestre
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,431
- **Award type:** 5
- **Project period:** 2023-09-01 → 2024-11-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908648

## Citation

> US National Institutes of Health, RePORTER application 10908648, Identifying Inflammatory Mediators of Clonal Hematopoiesis (5F99CA284253-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10908648. Licensed CC0.

---

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