Targeting the plasticity of mesenchymal stromal cells to reroute the course of acute myeloid leukemia

Giulia Borella, Ambra Da Ros, Giulia Borile, Elena Porcù, Claudia Tregnago, Maddalena Benetton, Anna Marchetti, Valeria Bisio, Barbara Montini, Barbara Michielotto, Alice Cani, Anna Leszl, Elisabetta Campodoni, Monica Sandri, Monica Montesi, Silvia Bresolin, Stefano Cairo, Barbara Buldini, Franco Locatelli, Martina Pigazzi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Bone marrow (BM) microenvironment contributes to the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell–cell interaction, and secretion of cytokines that during leukemogenesis are altered and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but >30% of patients still relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the role of mesenchymal stromal cells (MSCs) in the leukemic niche to define its contribution to the mechanism of leukemia drug escape. We generated a humanized 3-dimensional (3D) niche with AML cells and MSCs derived from either patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation and severely compromising their immunomodulatory capability. We confirmed that AML cells modulate h-MSCs transcriptional profile promoting functions similar to the AML-MSCs when cocultured in vitro, thus facilitating leukemia progression. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features at transcriptional and functional levels, including the secretome. We proved that AML blasts alter MSCs activities in the BM niche, favoring disease development and progression. We discovered that a novel AML-MSC selective CaV1.2 channel blocker drug, lercanidipine, is able to impair leukemia progression in 3D both in vitro and when implanted in vivo if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.
Lingua originaleEnglish
pagine (da-a)557-570
Numero di pagine14
RivistaBlood
Volume138
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • MESENCHYMAL STROMAL CELLS

Fingerprint

Entra nei temi di ricerca di 'Targeting the plasticity of mesenchymal stromal cells to reroute the course of acute myeloid leukemia'. Insieme formano una fingerprint unica.

Cita questo