KV11.1 (hERG1)-centered macromolecular membrane complexes regulate proliferation in B cell lymphomas and constitute novel pharmacological targets

K + channel modulation is essential to regulate the Ca 2+ signals that trigger T and B lymphocyte activation. The K + channel complement is however deeply altered in cancer cells, as it is implicated in the neoplastic progression. We investigated the functional expression of K + channels in different diffuse large B cell lymphoma (DLBCL) cell lines (SU-DHL-4, WSU-DLCL2, U2932) and EBV-infected lymphocytes, as controls of normally proliferating lymphocytes. We studied the K + channels best characterized in lymphocytes (the voltage-gated K V 1.3 and the Ca 2+ -activated K Ca 3.1) and two members of the ether-à-go-go (EAG) family (K V 11.1, or hERG1; K V 12.2, or hELK2) that are often overexpressed in cancer cells. All the above channel types were found in lymphoma cell lines. However, compared to normal lymphocytes, K V 1.3 and K Ca 3.1 tended to be substituted by EAG channels, and especially by hERG1. In all DLBCL models, cell adhesion to fibronectin stimulated the formation of the cancer-specific macromolecular complex between hERG1 and the β1 subunit of integrin receptors. No such complex was formed by hELK2. A strong reduction of lymphoma proliferation was produced when the hERG1-β1 integrin complex was disrupted by a bispecific antibody (scDb-hERG1-β1), or by the hERG1-binding macrolide antibiotic clarithromycin. Finally, in a cohort of mucosa-associated lymphoid tissue (MALT) lymphoma patients treated with clarithromycin, a trend for an improved overall survival probability was observed in patients expressing the hERG1-β1 integrin complex. Our results suggest that the hERG1-β1 integrin complex promotes lymphoma cells’ proliferation. Disrupting the complex by specific targeting agents represents a new therapeutic approach to be explored.