# Causes and consequences of genomic instability in myelodysplasia > **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $584,872 ## Abstract PROJECT SUMMARY/ABSTRACT Myelodysplastic syndromes (MDS) are a group of age-related marrow failure disorders characterized by cytopenia and anemia. It is estimated that 10,000 new cases of MDS are diagnosed in the United States each year. This is caused by the functional decline of hematopoietic stem cells in the marrow because of acquired genetic mutations that corrupt their ability to make blood cells effectively. Clinical management of MDS remains challenging with limited treatments available, and stem cell transplantation remains the only curative therapy. However, most patients are unable to receive transplantation due to advanced age and co- morbidities. Thus, there is a pressing need to better understand the complexity of the disease which can lead to the development of novel therapies. Somatic mutations in splicing factor genes including SRSF2, U2AF1, SF3B1 and ZRSR2 are found in most patients with MDS. Patients carrying splicing mutation are generally older, have inferior prognoses, and are at a higher risk of transforming to secondary leukemia. Recent studies found that mutations in splicing factor genes trigger an elevated level of cellular R-loops, which consists of a RNA:DNA hybrid structure and a displaced single-stranded DNA. While R-loops are natural by-products of active transcription, if left unresolved, they could pose as a threat to genome integrity due to their propensity to induce double strand breaks. Here, we propose to test the hypothesis that targeting R-loop-induced genomic instability is an attractive therapeutic strategy in MDS cells that carry endogenous mutations in RNA splicing factors. Our preliminary data suggest that cells mutated for splicing factors are exquisitely sensitive to clinically approved PARP inhibitors, such as Olaparib, and a novel PARP1-specific inhibitor, AZD5305. Moreover, we provide evidence that PARP can physically associate with R-loops to dampen R-loop-induced genomic instability, and that PARP1 activity at R-loops could be used as a predictive biomarker for PARP inhibitor response. This proposal has two specific aims. In Aim 1, we plan to dissect the underlying molecular mechanisms of PARP inhibitor sensitivity in the context of splicing mutant MDS, and to test the therapeutic potential of PARP inhibitors in pre-clinical MDS models. In Aim 2, we plan to expand and identify combination therapy strategies with PARP and PARP1-specific inhibitors. We first plan to determine whether that combining PARP and ATR inhibitors can induce synergistic effects in MDS cells with RNA splicing mutations. Next, we plan to identify and test novel sensitizers of PARP1-specific inhibitor to evaluate optimal combination treatment strategy using pre-clinical models. Successful completion of this proposal will lead to the validation of new treatment options that can hopefully improve the outcomes MDS patients. ## Key facts - **NIH application ID:** 10942010 - **Project number:** 1R01CA292932-01 - **Recipient organization:** FRED HUTCHINSON CANCER CENTER - **Principal Investigator:** Stanley Chun-Wei Lee - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $584,872 - **Award type:** 1 - **Project period:** 2024-09-01 → 2029-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10942010 ## Citation > US National Institutes of Health, RePORTER application 10942010, Causes and consequences of genomic instability in myelodysplasia (1R01CA292932-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10942010. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*