LIMK Inhibition and Metformin Block Mitochondrial Transfer Overcoming Macrophage Driven Therapy Resistance in Acute Myeloid Leukaemia
Year: 2026
Type: preprint
Abstract: ABSTRACT Chemoresistance is a major contributor to poor clinical outcomes in AML patients and can arise from interactions between AML cells and the bone marrow microenvironment (BME). How immune cells, particularly macrophages (Mφs), facilitate this process requires better clarification. This study shows that M2-like Mφs protect AML cells from apoptosis induced by daunorubicin (DNR) and cytarabine (Ara-C). This protection occurs via co-culture and is linked to enhanced mitochondrial transfer from Mφs to AML cells. Mφs interacted with AML cells via tunneling nanotube (TNT)-like structures. Furthermore, inhibition of mitochondrial transfer using cytochalasin B reduced the protective effect, indicating that mitochondria mediate this process. Mφs transferred functional mitochondria to AML cells as evidenced by enhanced metabolic capacity and reduced reactive oxygen species levels in AML cells under chemotherapy stress. TH-257 (LIMK inhibitor) and metformin blocked mitochondrial transfer and Mφ-driven chemoprotection. Moreover, increased transcript expression levels of RhoC and cofilin correlate with inferior overall survival in AML patients. These findings suggest that M2-like Mφs contribute to chemoresistance through TNT-mediated mitochondrial transfer and the LIMK-Cofilin pathway, identifying potential therapeutic targets to circumvent chemoresistance in AML.
Authors: Ebubechukwu Nwarunma, Katerina E. Miari, Athanasia Papadopoulou, Stefan Corradini, Glen Watt, Samantha Hurwitz, Tatiana Fourfouris, Ki Jun Lee, Xenia Bubnova, Rebecca Briggs, Carl S Goodyear, Theodoros Simakou, Marcus Doohan, Lucy MacDonald, Mariola S. Kurowska-Stolarska, Timothy J. Humpton, Victoria L. Campbell, Lesley M. Forrester, Ken I. Mills, Katrina Lappin, Valerie A. Ferro, Yong-Mi Kim, Helen Wheadon, Mark T.S. Williams
Institutions: Glasgow Caledonian University, University of Glasgow, University of Southern California, Children's Hospital of Los Angeles, Queen's University Belfast, Cancer Research UK Scotland Institute, Western General Hospital, MRC Centre for Regenerative Medicine, University of Edinburgh, University of Strathclyde
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G4089408261, G6026290327
OpenAlex ID: W7128061141