# MDS-associated U2AF1 mutations induce natural killer cell dysfunction

> **NIH CA R21** · NATIONAL JEWISH HEALTH · 2026 · $435,062

## Abstract

PROJECT SUMMARY/ABSTRACT
Therapeutic approaches that harness the immune system to target tumors are revolutionizing the cancer
treatment field. Natural Killer (NK) Cells are innate lymphocytes that regulate inflammatory and immune
responses and that directly and indirectly kill tumor cells. While NK cell-harnessing immunotherapies have
shown great promise as novel treatments for many cancers, NK cells are unable to efficiently kill tumor cells in
patients with Myelodysplastic Syndrome (MDS) and related hematological malignancies. This dysfunction
impairs immune surveillance, likely contributing to MDS pathogenesis and hindering the efficacy of novel NK
cell-harnessing immunotherapies. The molecular and cellular causes of this immune dysfunction have
remained enigmatic. In the current proposal, we are investigating the effects of mutations in the spliceosome,
which are the most common class of somatically acquired mutations in MDS patients. In preliminary studies,
we found that MDS-associated spliceosome mutations drive substantial NK cell dysfunction in mice and
humans. Based on these results, we hypothesize that MDS-associated spliceosome mutations impair NK cell
function by altering expression or functionality of critical NK cell-intrinsic gene products. We propose to
determine the cellular (Aim 1) and molecular (Aim 2) mechanisms underlying these effects. Understanding how
the most common class of mutations in MDS patients drives NK cell defects will provide critical mechanistic
insights needed to advance development of more targeted and effective immune-based therapies to treat MDS
and related malignancies.

## Key facts

- **NIH application ID:** 11302610
- **Project number:** 1R21CA301519-01A1
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Scott  Alper; Laurel L Lenz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $435,062
- **Award type:** 1
- **Project period:** 2026-04-01T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11302610

## Citation

> US National Institutes of Health, RePORTER application 11302610, MDS-associated U2AF1 mutations induce natural killer cell dysfunction (1R21CA301519-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11302610. Licensed CC0.

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