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 Ca2+ 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 KV1.3 and the Ca2+-activated KCa3.1) and two members of the ether-à-go-go (EAG) family (KV11.1, or hERG1; KV12.2, 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, KV1.3 and KCa3.1 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.