<i> IGLV3-21 <i>*</i> 01 </i> is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling
Palash Chandra Maity, Mayas Bilal, Marvyn T. Koning, Marc Young, Cornelis A.M. van Bergen, Valerio Renna, Antonella Nicolò, Moumita Datta, Eva Gentner-Göbel, Rob S. Barendse, Sebastiaan Somers, Ruben A. L. de Groen, Joost S.P. Vermaat, Daniela Steinbrecher, Christof Schneider, Eugen Tausch, Tamara Bittolo, Riccardo Bomben, Andrea Nicola Mazzarello, Giovanni Del Poeta, Wilma G. M. Kroes, Tom van Wezel, Katharina Imkeller, Christian E. Busse, Massimo Degano, Tamam Bakchoul, Axel Schulz, Henrik E. Mei, Paolo Ghia, Konstantia Kotta, Κώστας Σταματόπουλος, Hedda Wardemann, Antonella Zucchetto, Nicholas Chiorazzi, Valter Gattei, Stephan Stilgenbauer, Hendrik Veelken, Hassan Jumaa
Abstract
Significance CLL is characterized by autonomous B cell receptor (BCR) signaling. CLL subsets are empirically defined by sequence similarities of the BCR heavy chain. However, in the unfavorable subset 2, an acquired mutation (termed R110) in the light chain stimulates autonomous BCR signaling. This study demonstrates that the oncogenic R110 mutation dictates the unfavorable prognosis and is not restricted to the conventional subset 2. Interestingly, carriers of a particular light-chain allele ( IGLV3-21 * 01 ) are predisposed to develop CLL because this allele enables autonomous BCR signaling by R110 as a single-point mutation. Monoclonal antibodies permit convenient screening for R110-expressing CLL, showing that it is the largest immunologically defined CLL subset and an example of functional rather than empirical CLL subclassification.