K_V11.1 (hERG1)-centered macromolecular membrane complexes regulate proliferation in B cell lymphomas and constitute...

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 K_V1.3 and the Ca²⁺-activated K_Ca3.1) and two members of the ether-à-go-go (EAG) family (K_V11.1, or hERG1; K_V12.2, 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_V1.3 and K_Ca3.1 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.