# Lnk Regulatory Functions in Hematopoietic Stem Cells

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $605,461

## Abstract

Abstract
Although initially identified about 90 years ago, Fanconi Anemia (FA) remains a fatal genetic disease with few
therapeutic options. Patients with the genetic disorder FA exhibit developmental malformations, bone marrow
failure (BMF), and increased cancer susceptibility. Twenty-one FA genes cooperate in a genome stability
pathway that is essential for repair of DNA interstrand crosslink (ICL) damage and tolerance of replication stress.
The cell proliferative and survival defects in FA result in hematopoietic stem cell (HSC) exhaustion that
contributes to BMF. However, how FA pathway disruption selectively affects HSC function is not understood.
Signaling events that can reduce FA severity remain to be established. Importantly, interventions to mitigate FA
associated HSC defects do not exist, aside from allogeneic stem cell transplant. This R01 renewal is based on
our discovery that activation of cytokine/JAK signaling ameliorates the HSPC defects associated with FA.
Specifically, we showed that loss of LNK (or SH2B3), a critical negative regulator of cytokine/JAK signaling fully
restored hematopoietic stem/progenitor cell (HSPC) functions in FA mutant mice and prevented FA associated
genome instability. HSCs nullizygous for both Lnk and the central component of the FA pathway, Fancd2,
exhibited near normal repopulation and self-renewal capability in serial transplantation assays. Interestingly, LNK
did not play an overt role in repair of ICL DNA damage; rather, Lnk deficiency stabilized stalled replication forks
and alleviated replication stress that is characteristic of FA cells. These results were strongly associated with
increased HSC fitness, ex vivo growth, survival and genomic stability in FA HSPCs that harbored concomitant
Lnk deficiency. Here, we propose comprehensive and in-depth analyses on the role of LNK in FA pathogenesis
and therapy. In aim 1, we propose to study the mechanisms by which LNK-regulated signaling pathways stabilize
replication forks and mitigate replication stress. Moreover, the FA pathway is reported to play a critical role in
mitigating two types of endogenous genotoxic stress, oxidative DNA damage caused by reactive oxygen species
and aldehyde-induced DNA damage generated by cellular metabolism. Our preliminary data suggested that Lnk
deficiency reduces both types of stress. Thus, in aim 2 we will determine mechanism by which Lnk deficiency
alleviates endogenous genotoxic stress and preserves HSPC functions. Lastly and importantly, we will determine
if targeting LNK could be widely used as a FA suppressor in aim 3. Since mutations in the FA core complex
FANCA/C/G account for ~90% FA in humans, we plan to expand our studies to test if Lnk deficiency could
restore HSC function in Fanca/c/g deficient mice. This study will culminate in exploring therapeutic avenues of
inhibiting LNK to rescue hematopoietic defects in primary HSPCs from FA patients. To our knowledge, this
suppression of HSPC dysfunction in vivo w...

## Key facts

- **NIH application ID:** 10074581
- **Project number:** 5R01HL095675-12
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Wei Tong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $605,461
- **Award type:** 5
- **Project period:** 2009-07-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074581

## Citation

> US National Institutes of Health, RePORTER application 10074581, Lnk Regulatory Functions in Hematopoietic Stem Cells (5R01HL095675-12). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10074581. Licensed CC0.

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