# Molecular mechanisms for bone marrow failure and clonal progression during the innate immune response in Fanconi Anemia

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $355,637

## Abstract

The Fanconi DNA repair pathway is required for rescue of stalled or collapsed replication forks. Fanconi
Anemia (FA) is caused by inherited mutation of Fanconi genes. FA patients develop bone marrow failure (BMF)
in childhood, with survivors frequently developing clonal progression. We identified a role for emergency (stress)
granulopoiesis (EG) in BMF and clonal progression in FA. EG is an episodic process for granulocyte production
in response to infectious challenge. During EG, S phase is shortened and FancC and F expression increase.
 Unlike wild type mice, Fancc-/- mice did not develop granulocytosis upon stimulation of EG. Repeated EG
challenge in Fancc-/- mice induced either BMF, with apoptosis of HSC and progenitors, or clonal progression.
Treatment of Fancc-/- mice with an IL1-R antagonist protected them from these adverse consequences. IL1β is
an essential cytokine for EG; inducing myeloid lineage commitment, and G-CSF expression. During the S phase,
Atr activates p53 and apoptosis of cells with unrepaired replication fork damage. In Fancc-/- mice, Tp53-haplo-
insufficiency rescued granulocytosis during EG; delaying BMF but accelerating clonal progression. In Fancc-/-
mice, increasing activity of Atr/p53 occurred with each unsuccessful EG episode; associated with BMF. In
contrast, Atr/p53 activity decreased with consecutive, successful EG cycles in Fancc-/-Tp53+/- mice.
 We hypothesize unsuccessful PMN production in FA during EG prevents activation of unknown negative
regulatory pathways; sustaining cell cycle checkpoint activity and HSC/GMP expansion signals. This induces
BMF and accumulation of mutations that lead to clonal progression. We will pursue this through three aims:
 Aim 1: Define molecular triggers for termination of emergency granulopoiesis and the role of this
process in BMF in FA. We will investigate contribution of PMN density to apoptosis and BMF during
unsuccessful EG in Fancc-/- mice. The impact of PMN bone marrow density on known EG-related pathways will
be determined in Wt vs Fancc-/- mice, and novel pathways identified in non-biased studies.
 Aim 2: Identify events associated with emergency granulopoiesis-induced clonal progression in FA.
We will define events involved in clonal progression in Fancc-/- mice by studying leukemia suppressor pathways
that mediate EG termination and by non-biased approaches. Results will be compared to gene expression
profiles in CD34+ bone marrow cells from human Fanconi Anemia to identify potential translational targets.
 Aim 3: Investigate potential translational targets to delay BMF or clonal progression in FA. We will
determine the impact of novel pathways that are activated during EG on BMF and/or clonal progression in murine
genetic models. Relevant intermediates with small molecule inhibitors will be tested in pre-clinical studies.
 The goal of these studies is to define molecular mechanisms for BMF and/or clonal progression during
recurrent, unsuccessful EG attempts in FA. Th...

## Key facts

- **NIH application ID:** 10102241
- **Project number:** 5R01DK121354-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elizabeth Ann Eklund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,637
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102241

## Citation

> US National Institutes of Health, RePORTER application 10102241, Molecular mechanisms for bone marrow failure and clonal progression during the innate immune response in Fanconi Anemia (5R01DK121354-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10102241. Licensed CC0.

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