The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions
- Author(s)
- Lew, TE; van Delft, MF; Heitink, L; Cobbold, SA; White, CA; Bong, JAR; Hittmeyer, P; Zhu, AH; Vaibhav, V; Yousef, J; Dagley, LF; Riffkin, CD; Georgiou, A; Hilton, A; Huang, AS; Yuan, Y; Horton, MB; Dawson, MA; Roberts, AW; Huang, DCS;
- Journal Title
- Blood
- Publication Type
- Online publication before print
- Abstract
- 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) that 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.
- Department(s)
- Haematology; Laboratory Research
- Publisher's Version
- https://doi.org/10.1182/blood.2026033874
- Open Access at Publisher's Site
https://doi.org/10.1182/blood.2026033874- Terms of Use/Rights Notice
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Creation Date: 2026-10-12 05:40:47
Last Modified: 2026-10-12 05:41:16