# Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $48,883

## Abstract

Project Summary/Abstract
There is mounting evidence that ribosomes are more dynamic and heterogenous than previously described.
Advances in our understanding of ribosomal functions now paint a picture of ribosomes as critical regulators of
gene expression with unique compositions and highly specialized functions that can differ across tissue types.
Aberrant ribosome activity has been assessed in many tumor types and recurrent mutations in ribosomal proteins
have been reported in a number of cancers and ribosomopathies associated with cancer, such as T-ALL and
Diamond-Blackfan anemia. This can include changes in the fidelity and rate of translation, preferential translation
of certain transcripts over others, utilization of alternative start and stop codons, and overall changes in intra-
cellular ribosome content. Recent whole exome sequencing studies of 538 patients with chronic lymphocytic
leukemia (CLL) have identified recurrent missense mutations (~5%) at a hotspot region of ribosomal protein S15
(RPS15). RPS15 mutations often co-occur with TP53 aberrations (36%) and are enriched in del(17p) CLL (12%)
– abnormalities that are often carry poor prognoses and refractoriness to chemoimmunotherapy. Indeed,
mutation of RPS15 is associated with adverse prognosis and an increased risk of relapse following chemo-
immunotherapy, even in the absence of TP53 or del(17p) deletions. However, despite these compelling clinical
findings, there is a paucity of information regarding how RPS15 mutation influences CLL pathogenesis. We have
generated an array of unique tools for the proposed study of this essential protein that promise to unravel this
mechanism. This includes human CLL cell lines that are well characterized and carry genetic mutations that
reflect common CLL lesions, such as del(13q) and TP53, and that have been edited to express RPS15 mutations
relevant in CLL. We have also generated physiologically faithful Rps15 knock-in mice that restrict mutant
expression to B cells. Using these models to characterize the functional impact of this mutation on CLL
development and progression will certainly provide new directions for therapeutic intervention and will add to our
fundamental understanding of ribosome pathology. The proposed study seeks to thoroughly interrogate the
impact of RPS15 mutations on CLL biology through the following aims: 1) Characterize its influence on ribosomal
protein functions (such as ribosomal RNA synthesis, ribosome assembly, translation and extra-ribosomal
functions – namely, the MDM2-P53 ribosome surveillance pathway) in both healthy and malignant tissue; and
2) Determine its impact on cancer hallmarks such as proliferation and growth factor independence in vitro and
on tumorigenicity in vivo. Because RPS15 mutations engage the mRNA decoding site, we hypothesize that they
contribute to pathogenesis through aberrant translation of mRNA. The proposed experimental approaches
include complex and novel techniques such as ribosome c...

## Key facts

- **NIH application ID:** 10170297
- **Project number:** 5F31CA239443-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Catherine Gutierrez Moore
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,883
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170297

## Citation

> US National Institutes of Health, RePORTER application 10170297, Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia (5F31CA239443-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10170297. Licensed CC0.

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