Proton Channels in Normal and Malignant B Cells

Abstract

HVCN1 is the only mammalian voltage-gated proton channel, highly expressed in B cell cancers such as lymphoma and chronic lymphocytic leukaemia (CLL). In normal B cells, we showed that HVCN1 sustains ROS production by the NADPH oxidase, required for optimal B Cell Receptor (BCR) signalling. In malignant B cells, HVCN1 appears to sustain tumour growth, since HVCN1 downregulation impairs cell survival. We are currently addressing whether HVCN1 supports cancer cells via maintaining ROS production and BCR signalling. During our initial investigation on HVCN1 in B cells, we identified a shorter translational isoform of 253 aa, translated from a second initiation site 20 aa downstream from the first ATG. HVCN1 Short is specifically expressed by malignant B cells: we have evidence that it has different electrophysiological properties, such as conducting larger currents with faster activation kinetics after PMA stimulation. In addition, while HVCN1 Long is internalised with the BCR upon stimulation, HVCN1 short is not, indicating it could mediate proton currents constitutively, thus further helping tumour cells maintain their aberrant pH and sustaining BCR signalling.Support: Bennett Fellowship from Leukaemia and Lymphoma Research (ref n: 12002) to MC. NSF MCB-0943362, NIH R01-GM087507 to TD.