# Replication stress in hematopoiesis and lymphomagenesis

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $427,995

## Abstract

Summary
The hematopoietic system is particularly sensitive to stimuli that cause DNA replication stress,
which can result in DNA breaks. Defects in the ability to properly respond to this stress are
linked to a predisposition to hematologic malignancies, hematopoietic cell deficiencies, and
bone marrow failure. Recent advances include the identification of genes that respond to DNA
replication stress and a greater understanding of genes necessary for hematopoiesis of specific
lineages, but much remains unknown about both processes and how they intersect to cause
pathology. Moreover, DNA replication stress is observed in human cancers, is induced by
oncogenes such as Myc, causes DNA damage, and contributes to genome instability, but it
remains poorly understood. Smarcal1 and more recently, Zranb3 were identified and evaluated
biochemically and by in vitro studies to localize to replication forks and be critical for responding
to DNA replication stress. Smarcal1 and Zranb3 are fork remodelers and reverse replication
forks to allow repair of damaged DNA and rewind single-stranded DNA. Both Smarcal1 and
Zranb3 have similar functions, but biochemical differences are reported. However, the functions
of Zranb3 and Smarcal1 and whether they are redundant or complementary at times of
replication stress or have unique functions in vivo has not been explored. Recently, we
genetically demonstrated that Smarcal1 was essential for mediating the effects of acute DNA
replication stress on hematopoietic stem and progenitor cells and contributed to the
development of T cell lymphoma. Our preliminary data support the hypothesis that Zranb3
contributes to hematopoiesis and lymphomagenesis in ways distinct from Smarcal1, and that
Zranb3 and Smarcal1 together contribute to hematopoiesis and lymphoma development.
Therefore, we propose three Aims with in vivo genetic approaches to test this hypothesis. 1)
Investigate the role of Zranb3 in Myc-induced replication stress and its contribution to acute and
chronic replication stress-induced lymphoma development. 2) Determine the role of Zranb3 in
hematopoiesis and hematopoietic stem and progenitor cell replication stress. 3) Evaluate the
combined loss of function of Zranb3 and Smarcal1 in hematopoiesis and lymphomagenesis.
Innovative concepts are tested with a new mouse model and multiple approaches, including
high-resolution genome wide end-sequencing. Completion of these Aims will significantly
advance understanding into DNA replication stress proteins and their contribution to genome
stability, hematopoiesis, and hematological malignancies.

## Key facts

- **NIH application ID:** 10057366
- **Project number:** 5R01CA226432-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** CHRISTINE M. EISCHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,995
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057366

## Citation

> US National Institutes of Health, RePORTER application 10057366, Replication stress in hematopoiesis and lymphomagenesis (5R01CA226432-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10057366. Licensed CC0.

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