The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy... Show moreThe prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify similar to 30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LC5), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21(R110)), we show that IGLV3-21(R110)-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a stand-alone driver that transforms IGLV3-21*01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21(R110)-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21(R110) facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors. Show less
Koning, M.T.; Ubelhart, R.; Zeeuw, S. van der; Kielbasa, S.; Jumaa, H.; Vermeer, M.; ... ; Veelken, H. 2017
Objectives: Deficiency of secreted IgM antibodies (sIgM-/-) in Ldlr-/- miceresults in accelerated atherosclerosis. However, the underlying mechanismshave not been elucidated.We aim to identify... Show moreObjectives: Deficiency of secreted IgM antibodies (sIgM-/-) in Ldlr-/- miceresults in accelerated atherosclerosis. However, the underlying mechanismshave not been elucidated.We aim to identify mechanisms by whichsecreted IgM deficiency results in increased lesion formation. Show less
Schneider, D.; Duhren-von Minden, M.; Alkhatib, A.; Setz, C.; Bergen, C.A.M. van; Benkisser-Petersen, M.; ... ; Jumaa, H. 2015
