# Genetic Determinants of Radiation induced Hematologic Toxicity

> **NIH NIH R21** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2021 · $230,244

## Abstract

SUMMARY
 Depletion of circulating lymphocytes, hematologic toxicity, is a common accompaniment of multimodal cancer
therapy. Lymphocytes are the most radiosensitive cells of the hematopoietic system. Radiation-induced
depletion of circulating lymphocyte counts have a significant impact on overall survival outcomes for many solid
cancers. This suggests that the immune system plays an important role in improving the efficacy of radiation
therapy. Understanding the causes of radiotherapy induced hematologic toxicity will allow the development of
novel strategies to predict, prevent and ameliorate this phenomenon and potentially improve patient outcome.
 The use of mice as model organisms for immunology research has led to significant advances in our
understanding of the mechanisms governing human immune activation and regulation, as well as
dysregulation. However, most mice studies use inbred strains with limited genetic diversity and do not reflect
the diverse responses observed in humans. The Collaborative Cross (CC) was designed to overcome these
limitations by modeling the genetic diversity found in the human population in a controlled and reproducible
manner. Using the CC mouse resource, we have collected acute and persistent radiation sensitivity data in 983
CC mice covering 17 CC strains. Our preliminary QTL analysis identified several genetic loci associated with
radiation sensitivity. One small, but highly significant QTL associated with acute radiation sensitivity of
lymphocytes, B- and T-cells was located on distal chromosome 1 and encompassed only the Ush2A gene
strongly suggesting that variations in this gene contribute to radiation sensitivity. Understanding the genes
affecting immune system cells and treatment associated hematologic toxicity is the first step in developing novel
therapies that are personalized according to an individual’s genetic make-up.
 In this proposal we will increase power of genetic detection of radiation sensitivity QTL, by expanding our
existing radiation induced hematologic toxicity data set with an additional 13 CC strains. In aim 1 we will test the
hypothesis that genetic variation and sex significantly influence radiation sensitivity of specific lymphocyte
populations and blood parameters. In aim 2, we will test the role of Ush2a, identified in our preliminary QTL
analysis in CC mice, in contributing to hematologic toxicity after radiation exposure. The identification of genetic
markers associated with radiation sensitivity in our mouse cohort will result in a greater understanding of
radiotherapy-induced lymphopenia, which may help design new therapeutic approaches to counter the effect.
The Collaborative Cross immunophenotypic and radiation response data resource will become a valuable tool
for the broad research community and will allow for association analysis among multiple complex phenotypes to
address the contribution of the immune system in health and disease.

## Key facts

- **NIH application ID:** 10219926
- **Project number:** 5R21AI145390-02
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Antoine M Snijders
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $230,244
- **Award type:** 5
- **Project period:** 2020-07-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219926

## Citation

> US National Institutes of Health, RePORTER application 10219926, Genetic Determinants of Radiation induced Hematologic Toxicity (5R21AI145390-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219926. Licensed CC0.

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