PXD083051

PXD083051 is an original dataset announced via ProteomeXchange.

Title	Targeting JAK2-V617F stability through TRIM4 recruitment reveals a therapeutic vulnerability in myeloproliferative neoplasms
Description	JAK2-V617F is a key oncogenic driver in myeloproliferative neoplasms (MPNs), yet mechanisms governing its protein stability and strategies for its degradation remain incompletely understood. Here, we employed an integrated screening strategy combining deubiquitinase and E3 ligase functional libraries with immunoprecipitation–mass spectrometry profiling of JAK2-V617F-associated proteins to identify regulators of mutant JAK2 stability. This approach revealed TRIM4 as a previously unrecognized E3 ligase that interacts with JAK2-V617F and promotes its ubiquitination, thereby facilitating proteasomal degradation and reducing protein stability. To explore therapeutic opportunities targeting this axis, we performed ligand discovery for TRIM4 and identified small molecules that modulate JAK2-V617F turnover. Among these, Tripterine acts as a TRIM4 recruiter to facilitate TRIM4–JAK2-V617F engagement, enhance mutant JAK2 ubiquitination, and accelerate ubiquitin–proteasome-mediated degradation of JAK2-V617F. Functionally, Tripterine suppresses proliferation of JAK2-V617F–mutant leukemia cells in vitro. Clinically, elevated TRIM4 expression correlates with adverse clinical outcomes in MPN/AML, particularly in JAK2-V617F–positive MPN. In patient-derived cellular models and JAK2-V617F–driven mouse models, Tripterine suppresses malignant cell growth ex vivo and attenuates disease progression in vivo. Collectively, these findings define a TRIM4-dependent regulatory mechanism controlling JAK2-V617F stability and identify Tripterine as a small-molecule modulator of this pathway with therapeutic relevance in MPN.
HostingRepository	iProX
AnnounceDate	2026-08-20
AnnouncementXML	Submission_2026-08-24_02:16:37.674.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaotong Chen
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-24 02:16:14	ID requested
⏵ 1	2026-08-24 02:16:38	announced

Dataset with its publication pending

submitter keyword: JAK2-V617F, TRIM4, Tripterine, E3 ligase recruitment, Targeted protein degradation, Myeloproliferative neoplasms (MPN)

Jing Yang
contact affiliation	School of Life Sciences and Technology, Tongji University
contact email	jingy@tongji.edu.cn
lab head
Xiaotong Chen
contact affiliation	School of Life Sciences and Technology, Tongji University
contact email	cxtong972@163.com
dataset submitter

iProX dataset URI