PXD070253-1

PXD070253 is an original dataset announced via ProteomeXchange.

Title	Oncogenic SF3B1 mutations alter the splicing of mRNA non-coding regions to induce a novel therapeutic vulnerability
Description	Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL) and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of mRNA protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss-of-function, thus contributing to cancer pathogenesis. Here we systematically analyzed the impact of mutant SF3B1 on non-coding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of one target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5’ and 3’ untranslated regions (5’, 3’ UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1 mutant cells, representing the first time that oncogenic SF3B1 has been shown to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.
HostingRepository	PRIDE
AnnounceDate	2026-01-27
AnnouncementXML	Submission_2026-01-27_13:18:58.939.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoyu Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-03 15:02:19	ID requested
⏵ 1	2026-01-27 13:18:59	announced

10.1182/BLOOD.2025029972;

submitter keyword: DCAF16,SF3B1

Sydney X. Lu, Xiaoyu Zhang
contact affiliation	Division of Hematology, Department of Medicine, Stanford University School of Medicine Department of Chemistry, Northwestern University
contact email	zhang@northwestern.edu
lab head
Xiaoyu Zhang
contact affiliation	Northwestern University
contact email	zhang@northwestern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD070253
     1. Label: PRIDE project
     2. Name: Oncogenic SF3B1 mutations alter the splicing of mRNA non-coding regions to induce a novel therapeutic vulnerability