Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Claudia Minici, Maria Gounari, Rudolf Übelhart, Lydia Scarfò, Marcus Dühren- von Minden, Dunja Schneider, Alpaslan Tasdogan, Alabbas Alkhatib, Andreas Agathangelidis, Stavroula Ntoufa, Nicholas Chiorazzi, Hassan Jumaa, Kostas Stamatopoulos, Paolo Ghia () and Massimo Degano ()
Additional contact information
Claudia Minici: Biocrystallography Unit, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Maria Gounari: B-cell Neoplasia Unit, IRCCS San Raffaele Scientific Institute
Rudolf Übelhart: Universitätsklinik Ulm
Lydia Scarfò: Università Vita-Salute San Raffaele
Marcus Dühren- von Minden: Universitätsklinik Ulm
Dunja Schneider: Centre for Biological Signaling Studies, Faculty of Biology, Albert-Ludwigs University of Freiburg
Alpaslan Tasdogan: Universitätsklinik Ulm
Alabbas Alkhatib: Centre for Biological Signaling Studies, Faculty of Biology, Albert-Ludwigs University of Freiburg
Andreas Agathangelidis: B-cell Neoplasia Unit, IRCCS San Raffaele Scientific Institute
Stavroula Ntoufa: Institute of Applied Biosciences, Center for Research and Technology
Nicholas Chiorazzi: The Feinstein Institute for Medical Research
Hassan Jumaa: Universitätsklinik Ulm
Kostas Stamatopoulos: Institute of Applied Biosciences, Center for Research and Technology
Paolo Ghia: Università Vita-Salute San Raffaele
Massimo Degano: Biocrystallography Unit, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR–BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.

Date: 2017
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DOI: 10.1038/ncomms15746

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