# Cooperation of SF3B1 mutations and ATM deletions in the pathogenesis of chronic lymphocytic leukemia

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $428,050

## Abstract

Project Summary
World-wide sequencing efforts have identified recurrent novel genetic lesions associated with disease
progression, inferred patterns of common co-occurrence, and characterized clonal evolution in response to
treatments in chronic lymphocytic leukemia. Despite the wealth of available genetic information, these analyses
all rely on statistical inference, thus limiting the possibility to link the genotype to the phenotype. Currently,
understanding functions of high frequency genetic lesions and how they cooperate with their co-occurring
mutations to cause CLL initiation and progression are not available. In this proposal, we aim to understand how
two of the most recurrent genetic lesions in CLL (SF3B1 mutations and ATM deletions) mechanistically impact
CLL initiation and progression with the overarching goal to understand CLL biology, generate novel murine
model, and find new strategies for treating CLL with these lesions.
This proposal is based on our finding that co-expression of mutated Sf3b1 with Atm deletion resulted in the
development of clonal pathognomonic CD19+CD5+ B cells in blood, marrow and spleen at low penetrance in
aged (18 months) mice, that can be propagated by in vivo passaging. Interestingly, whole-genome sequencing
of DNA from murine CLL revealed recurrent chromosome amplifications, suggesting chromosome instability as
a mechanism contributing to CLL in the mice with Sf3b1 mutation and Atm deletion. We now propose to
investigate the hypothesis that SF3B1 mutations promote genomic instability through RNA splicing related R-
loop formation while ATM deletion further augment genomic instability through decreasing R-loop associated
DNA damage repair (Aim 1). We further hypothesize that modulation of the R-loop formation is contributing to
the acceleration of CLL (Aim 2). Thus, targeting both RNA splicing and DNA damage response checkpoints are
likely to provide synthetic cytotoxicity for CLLs with these lesions (Aim 3). Completion of the proposed work will
create a fundamental foundation to explain how splicing factor mutations impact genomic instability and
contribute to oncogenesis, and provide rationale for designing novel clinical trials in CLL patients with both SF3B1
mutations and ATM deletions.

## Key facts

- **NIH application ID:** 10116331
- **Project number:** 5R01CA240910-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Lili Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $428,050
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116331

## Citation

> US National Institutes of Health, RePORTER application 10116331, Cooperation of SF3B1 mutations and ATM deletions in the pathogenesis of chronic lymphocytic leukemia (5R01CA240910-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10116331. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*