# Constrained Fetal Hematopoiesis and Clonal Restriction in Fanconi Anemia

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $622,503

## Abstract

Summary
This proposal explores a new model of Fanconi Anemia (FA) pathogenesis based on our findings that FA
proteins protect hematopoietic stem cells (HSCs) from replication stress during the rapid developmental
expansion in the fetal liver (FL). FA is a recessively inherited DNA repair disorder with cancer predisposition
and near uniform bone marrow (BM) failure. While most FA patients experience symptomatic failure in early
school age, BM hematopoietic stem cell (HSC) numbers are already compromised much earlier in life. We
recently reported that the physiologic onset of HSC deficits in FA knockout mice occurs in utero. We now
show that deficits in FA first emerge in the FL, caused by replication stress-associated Atr/Chk1 checkpoint
engagement in immunophenotypically defined HSC. Because the HSC pool is typically complete at birth,
these constraints constitute not only a previously unrecognized bottleneck for HSC pool formation in FA, but
also pose a principal risk factor for rapid postnatal HSC exhaustion. To understand the exaggerated
developmental vulnerability in the FA FL we have conducted additional preliminary studies of the FL
microenvironment that implicate a subset of supportive cells forming the HSC niche. Altogether, we
hypothesize that the physiological role of FA proteins is to safeguard in HSC pool clonality and genome
integrity under conditions of replication stress. These observations lead us to test the long-term impact of
fetal deficits in FA on HSC self-renewal and hematopoietic reserve.
Specific Aim 1 ïDetermine absolute HSC pool size and clonal diversity as driving risk factors for
 HSC exhaustion in FA
Specific Aim 2 ïDissect the long-term impact of checkpoint activation on genome stability and
 function in fetal FA HSC
Specific Aim 3 ïIdentify the FL specific niche abnormalities that contribute to hematopoietic deficits
 in FA, and reveal the key signaling pathways that functionally limit HSC expansion
Altogether, this project advances a new paradigm, whereby FA proteins enable developmental expansion
and self-renewal divisions critical to clonal diversity and genome stability in the HSC pool. This positions
developmental deficits in FA patients as a driving risk factor for HSC exhaustion and a critical cause for
morbidity and mortality. Results will provide insight for the development of safe and effective new therapies
that mitigate loss of hematopoietic function in FA.

## Key facts

- **NIH application ID:** 10133727
- **Project number:** 5R01HL150882-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Peter Kurre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $622,503
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133727

## Citation

> US National Institutes of Health, RePORTER application 10133727, Constrained Fetal Hematopoiesis and Clonal Restriction in Fanconi Anemia (5R01HL150882-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133727. Licensed CC0.

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