Serena Pillozzi1, Marika Masselli1, Emanuele De Lorenzo1, Benedetta Accordi2, Emanuele Cilia1, Olivia Crociani1, Amedeo Amedei3, Marinella Veltroni2, Massimo D'Amico1, Giuseppe Basso2, Andrea Becchetti4, Dario Campana5, Annarosa Arcangeli1
1Department of Experimental Pathology and Oncology, University of Firenze, Firenze, Italy;
2Oncohematology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy;
3Department of Internal Medicine, University of Firenze, Firenze, Italy
4Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano Bicocca, Italy; and
5Departments of Oncology and Pathology, St Jude Children's Research Hospital, Memphis, TN
Tóm tắt
Abstract
Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β1-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.
