PXD082032-1

PXD082032 is an original dataset announced via ProteomeXchange.

Title	The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein–protein interactions
Description	The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria–ER contact sites (MERCS) restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein–protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.
HostingRepository	PRIDE
AnnounceDate	2026-09-10
AnnouncementXML	Submission_2026-09-09_18:22:38.523.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Laura Gianni
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	ubiquitination signature dipeptidyl lysine; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-02 19:00:32	ID requested
⏵ 1	2026-09-09 18:22:39	announced

10.1182/BLOOD.2026033874;

submitter keyword: hematological malignancies, resistance, BCL2, UBE2J2, MFN2, apoptosis,MARCH5

Dr. Thomas Lew
contact affiliation	Division of Blood Cells and Blood Cancer The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade, Parkville Victoria, Australia, 3050
contact email	lew.t@wehi.edu.au
lab head
Laura Gianni
contact affiliation	WEHI
contact email	dagley.l@wehi.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD082032
     1. Label: PRIDE project
     2. Name: The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein–protein interactions