Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones

Yun Liu¹Dzmitry Padhorny²Rosa Catera¹Antonella Nicolo³Xiao-Jie Yan¹Stan Xiaogang Li⁴Anastasia Iatrou⁵Steven L Allen¹Jonathan Kolitz¹Kanti R Rai¹Massimo Degano⁶Paolo Ghia⁶Charles C Chu¹Florian Krammer⁷Hassan Jumaa³KOSTAS STAMATOPOULOS⁵Dmytro Kozakov⁴Nicholas Chiorazzi^1*

• ¹Feinstein Institute for Medical Research, New York, New York, United States
• ²Stony Brook University, Stony Brook, New York, United States
• ³Ulm University Medical Center, Ulm, Germany
• ⁴Stony Brook Medicine, Stony Brook, New York, United States
• ⁵Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece, Thessaloniki, Greece
• ⁶Vita-Salute San Raffaele University, Milan, Lombardy, Italy
• ⁷Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

Immunoglobulins (IGs) made by chronic lymphocytic leukemia (CLL) B cells are unique in that they bind themselves (homo-dimerize). This interaction leads to signal transduction with functional consequences that depend on the affinity of homo-dimerization. We have studied the antigen-binding properties of the IGs from a subset of patients with CLL (Subset #4) that homo-dimerize at high affinity. Previously, we had found that subset #4 IGs bound viable lymphocytes. Our new studies, probing an array of >8,000 antigens, indicate that these IGs also bind influenza virus. Because of the IGs high-affinity homo-dimerization, we asked if the defined foreign-and self-antigenic interactions were mediated by conventional B-cell receptor (BCR) domains or a non-conventional receptor created by homo-dimerization. The studies indicated the latter since abrogation of homo-dimerization eliminated binding to influenza virus and its hemagglutinin and to viable lymphocytes. Using these findings, we modeled a developmental path whereby a naive IgM + B cell with subset #4 heavy and light chain variable domains used the conventional BCR to interact with auto-and foreign antigens and acquire homo-dimerization capacity to create the non-conventional antigen-receptor when transitioning to a leukemic cell. Future studies will determine if this process is an idiosyncratic occurrence or a physiologic principle.