P058 | Characterization of Mesenchymal Stem Cells Reveals Potential Mechanisms of Relapse in Npm1-mutated Acute Myeloid Leukemia
Year: 2025
Type: article
Abstract: Background: one-third of adults with AML harbor the NPM1 mutation (NPM1mut). Despite a favorable prognosis, co-mutations contribute to heterogeneity and relapse rates of up to 50%. This may be due to interactions between chemo-resistant leukemic cells and bone marrow (BM) mesenchymal stem cells (MSCs). Aim: to characterize MSCs from AML-NPM1mut patients and identify mechanisms of therapy resistance/relapse. Methods: In this prospective study, MSCs were isolated from BM of AML patients at diagnosis (T0), remission (T1), and from healthy donors (HDs). MSC morphology, proliferative/differentiation capacity, surface antigen expression, and ROS levels were assessed. AML- and HD-MSCs were co-cultured with NPM1mut OCI-AML3 cells to evaluate changes in ROS, surface markers, proliferation, and BM-niche interactions (CXCR4/SDF1 axis, CD49d). Results: 82 AML and 20 HD samples were analyzed; 26 AML pts had NPM1mut (31.7%). Of these, 20 achieved remission and 8 relapsed. Currently, 21 AML-NPM1mut pts (80.7%) are alive. Despite similar proliferative capacity, AML-NPM1mut MSCs reached senescence earlier than HD-MSCs at T0 (p=0.0012) and T1 (p=0.0025). No other statistically significant differences were observed. In the co-culture assays, at T0 AML-NPM1mut MSCs produced ROS levels inversely proportional to blast counts (p 0.044) and OCI-AML3 expressed higher CD49d levels when exposed to AML-NPM1mut MSCs compared to AML-NPM1wt MSCs (p=0.0283). At the same timepoint, SDF1 plasma levels were lower in AML-NPM1mut than AML-NPM1wt (p<0.0001). Furthermore, in AML-NPM1mut samples SDF1 levels were higher during remission than at diagnosis (p=0.002). Conclusion: our preliminary data suggest that MSCs of AML-NPM1mut pts have an impaired stress response: they reach senescence earlier and produced less ROS levels when exposed to stressors. This may be due to an underlying mitochondrial dysfunction and a shift in the redox balance coupled with maladaptive antioxidant defences. In addition, OCI-AML3 cells exposed to MSCs expanded from AML-NPM1mut had a higher surface expression of CD49d. Furthermore, increased SDF1 binding to CXCR4 could explain the lower levels of plasma SDF1. This suggests that in vivo AML-NPM1mut MSCs’ homing ability is preserved and supports the hypothesis that AML-NPM1mut relapse could derive from cell-adhesion mediated drug resistance of AML blasts.
Authors: L. Calabretta, C. Valsecchi, S. Croce, G. Martini, C.P. Tobar Cabrera, E. Gelli, G. Riccaboni, A. De Silvestri, E. Roncoroni, P. Zappasodi, M.A. Avanzini, M. Rossi
Institutions: University of Pavia, Policlinico San Matteo Fondazione
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093121710
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