# Therapeutic Targeting of Transcription-Driven Epigenetic Defects in SF3B1 Mutant Myelodysplastic syndromes (MDS)

> **NIH NIH K08** · YALE UNIVERSITY · 2024 · $169,548

## Abstract

PROJECT SUMMARY/ABSTRACT:
This proposal for a Mentored Clinical Scientist Research Career Development Award (K08) outlines a
comprehensive training program for the career development of the applicant Dr. Prajwal Boddu as an
independent physician scientist. The focus of scientific investigation is myelodysplastic syndrome (MDS), the
most common cause of bone marrow failure in adults. Mutations in well-defined groups of genes (splicing factors,
epigenetic regulators) underlie most MDS. SF3B1 mutations are most common among splicing factors,
accounting for about 20% of MDS cases. Conventional models assign disruption of alternative splicing to be the
primary cause of splicing factor mutant MDS, but many limitations to these studies have prompted alternate
hypotheses. In this application, we consider an additional context in which splicing factors function – specifically,
their role in the regulation of RNA transcription. Given the close interplay between RNA transcription and splicing,
we explored how SF3B1 mutations affect transcription kinetics. Our studies show that SF3B1 mutations disrupt
RNA Polymerase II (Pol II) transcription, leading to a profound reshaping of chromatin architecture, and yielding
targetable epigenetic modifications. Consequently, we redefine SF3B1-mutant MDS functionally as an epigenetic
disorder. Based on these preliminary results, this proposal will delve into the molecular mechanisms that link
SF3B1 mutations to Pol II elongation defects and altered chromatin accessibility. The first aim will explore a novel
hypothesis that mutant SF3B1 impairs early spliceosome assembly, affecting Pol II density at gene promoters,
ultimately leading to chromatin closure and altered gene expression. The second aim will investigate the impact
of these transcription defects on higher order chromatin (3D genome). Recent studies have pointed to the link
between 3D genome reorganization and clonal evolution and aberrant gene expression patterns in many clonal
processes. The third aim seeks to leverage data from an unbiased screen that shows reversal of transcription
defects through inhibition of chromatin modulators such as those in the Sin3/HDAC complex. Using patient
derived xenograft (PDX) models, we will explore therapeutic targeting of these chromatin modulators. The
application seeks to expand the principal investigator’s training in RNA splicing, transcription biology, and
epigenetics under the mentorship of Dr. Manoj Pillai, a physician scientist with expertise in RNA mechanisms
and hematopoiesis, alongside co-mentor Dr. Karla Neugebauer, a pioneer in the field of co-transcriptional
splicing. Additional expertise will be provided by an advisory committee comprising of Drs Andrew Xiao
(epigenetics) and Amit Verma (patient-derived xenograft modeling and pre-clinical studies of MDS). Yale
University provides exceptional opportunities for both training and career development for aspiring physician
scientists such as Dr. Boddu. A carefully ...

## Key facts

- **NIH application ID:** 10948551
- **Project number:** 1K08DK140636-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Prajwal Boddu
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,548
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948551

## Citation

> US National Institutes of Health, RePORTER application 10948551, Therapeutic Targeting of Transcription-Driven Epigenetic Defects in SF3B1 Mutant Myelodysplastic syndromes (MDS) (1K08DK140636-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10948551. Licensed CC0.

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