PXD071901-1

PXD071901 is an original dataset announced via ProteomeXchange.

Title	Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability
Description	Ribosomal protein mutations are increasingly associated with cancer risk and thought to perturb ribosome function. At the same time, they reportedly activate p53, a critical anti-cancer barrier. To determine how these mutations overcome this protective block to enable tumorigenesis, we generated an in vivo model of the hotspot Rps15-S138F mutation identified as a putative driver of chronic lymphocytic leukemia. Under pre-leukemic conditions, this mutation induced protein instability, ribosome biogenesis defects and altered translation resulting in oxidative stress, DNA damage and induction of a p53-dependent response that promote initial cellular hypo-proliferation. However, aged mice with mutated Rps15 eventually developed B-cell leukemia (37% penetrance), which exhibited increased Myc activity with strong pro-survival and proliferation signatures. Mutant Rps15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis. In support of paired RNA-seq and ribo-seq profiling of age-matched Rps15-S138F mutant and wildtype mice, proteomics analyses were conducted to discover genes with differential translational efficiencies. In our pre-leukemic models, key genes involved in ameliorating oxidative stress and regulating DNA damage response are detrimentally affected with reduced translation efficiency, whereas genes regulating cell cycle and and translation initiation exhibited increased translation efficiency–underscoring the interplay of hypoproliferative and hyperproliferative signals present in Rps15-mutated cells in advance of leukemic transformation.
HostingRepository	PRIDE
AnnounceDate	2026-06-01
AnnouncementXML	Submission_2026-05-31_16:18:30.124.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Neil Ruthen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; EASY-nLC 1000

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-11 22:24:33	ID requested
⏵ 1	2026-05-31 16:18:30	announced

10.1038/s41467-026-70655-1;

Gutierrez C, Kwok M, Ruthen N, Waddicor P, Curran C, Ouspenskaia T, Fu D, Smalec B, Sedor S, Knisbacher BA, Biran A, Nagler A, Garbicz F, Sewastianik T, Penailillo J, Lucas F, Yin S, Liani A, Chen S, Lazarian G, Witten E, Dangle N, Brunsting EL, Zheng M, Lin ES, Lee MJ, Wells B, Pomerance L, Hern, á, ndez-S, á, nchez M, Li S, Lin Z, Al'Khafaji A, Wang L, Thakurela S, Livak KJ, Neuberg D, Cymbalista F, Getz G, Regev A, Churchman S, Ten Hacken E, Carrasco R, Shao S, Wu CJ, Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability. Nat Commun, 17(1):(2026) [pubmed]

submitter keyword: Mouse, Ribosomal protein mutations, Chronic Lymphocytic Leukemia

Catherine J. Wu
contact affiliation	Dana-Farber Cancer Institute
contact email	catherine_wu@dfci.harvard.edu
lab head
Neil Ruthen
contact affiliation	Weill Cornell Graduate School of Medical Sciences
contact email	ner4001@med.cornell.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071901
     1. Label: PRIDE project
     2. Name: Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability