# Role of FA Proteins in Hematopoiesis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $397,500

## Abstract

Abstract
Fanconi anemia (FA) is the most common type of inherited bone marrow failure (BMF) syndromes
and poses tremendous challenges in health care. The process of FA disease progression in the
context of hematopoiesis is characterized by BMF, clonal proliferation of hematopoietic stem and
progenitor cells (HSPCs), and progression to myelodysplastic syndrome (MDS) and acute
myeloid leukemia (AML). While many studies have established a correlation between FA deficiency
and defects in the HSC compartment, the mechanisms by which the FA proteins function in HSC
maintenance remain largely unknown. During this past funding period, we have gathered
evidence implicating pathogenic role of HSC-specific metabolic abnormality in FA. More recently,
we identified the Fancd2-Atad3-Tufm complex using our newly developed Fancd23XFLAGHA knock-
in model, and established a potential linkage of FA HSC failure to dysregulated mitochondrial
translation and oxidative phosphorylation (OXPHOS). We hypothesize that the FANCD2/FA
pathway restricts mitochondrial activity in HSC maintenance, and that loss of FA function
leads to augmented mitochondrial translation and OXPHOS contributing to BMF and
leukemic progression. The goals of the project are to investigate (1) the mechanism by which
the FANCD2/FA pathway controls mitochondrial activity in HSC maintenance and (2) the link
between augmented mitochondrial translation/OXPHOS and FA disease progression. To achieve
these goals, we will first assess the functional consequence of the interaction between Fancd2
and the mitochondrial translational machinery by determining the structural elements of the
biochemical interaction between Fancd2 and the Atad3-Tufm complex, the requirement for the
Fancd2-Atad3-Tufm interaction in the control of mitochondrial translation and OXPHOS, and the
functional link between the Fancd2-Atad3-Tufm interaction and HSC maintenance. We will then
investigate whether there is a direct link between augmented mitochondrial translation/OXPHOS
and FA disease progression in FA patients at three different stages (BMF, MDS, and AML), and
the cellular mechanisms responsible for leukemic transformation in FA HSCs. Successful
completion of the proposed study will not only improve mechanistic understanding of the interplay
between the FA pathway and mitochondrial metabolism in the context of HSC maintenance, but
also lead to a new avenue of research designed to target specific dysregulated metabolic
checkpoints for developing innovative therapeutic strategies in FA and other BM failure and
leukemia diseases.

## Key facts

- **NIH application ID:** 9939646
- **Project number:** 5R01HL076712-13
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** QISHEN PANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2005-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939646

## Citation

> US National Institutes of Health, RePORTER application 9939646, Role of FA Proteins in Hematopoiesis (5R01HL076712-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939646. Licensed CC0.

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