P48 | NEW STRATEGIES TO IMPROVE THE RESPONSE OF AML CELLS TO TARGETED THERAPIES BY OVERCOMING THE PROTECTIVE EFFECT OF THE BONE MARROW MESENCHYMAL STEM CELLS

G. Mazzanti¹, F. Liccardo², L. Pace¹, M. Marcotulli³, L. Lafrate³, G. Cidonio³, T. Ottone⁴, S. Travaglini⁴, M.T. Voso⁴, V. Fulci⁵, M. Sampaolesi¹, F. Fazi¹, S. Masciarelli¹ | ¹Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences and Medical Embryology, Section of Histology Sapienza University of Rome, Rome, Italy; ²Centre de Recherches en Cancérologie de Toulouse, Inserm/ U1037, Université de Toulouse, Toulouse, France; ³Department of Mechanical and Aerospace Engineering, Sapienza University of Rome, Rome, Italy; ⁴Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy; ⁵Department of Molecular Medicine, Sapienza, University of Rome, Rome, Italy

Drug resistance and relapses are significant issues for the success of targeted therapies for acute myeloid leukemia (AML), rendering the rate of cure unsatisfying. This is primarily due to clonal selection and the protective effect of the bone marrow microenvironment (BM)¹. Accordingly, we demonstrated that BM mesenchymal stem cells (MSCs) protect AML cells from the Azacytidine + Venetoclax (AV) treatment (an established standard of care for AML patients²) as well as from a strategy that we previously developed, inducing proteotoxic and oxidative stress using Retinoic acid, Bortezomib and Arsenic trioxide (RBA)³. Thus, we added the Bcl-2 inhibitor Venetoclax to the combination RBA (RV) to treat AML cells in mono or co-culture with MSCs in 2D and 3D models. We assessed that the combination RV overcomes the MSCs protection and significantly prolongs the life span of a murine model of human AML. To study the mechanisms underlying the crosstalk between AML and MSCs, we analyzed the morphology of the MSCs after treatment of co-cultures with AV and RV by immunofluorescence analysis and live-cell imaging. Furthermore, we performed proteomic analysis, revealing the involvement of molecular pathways related to extracellular matrix reorganization, highlighting a possible role of the actin cytoskeleton in this protective crosstalk.