IGLV3-2101 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling
The 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 supe...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 8; pp. 4320 - 4327 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington
National Academy of Sciences
25.02.2020
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Subjects | |
Online Access | Get full text |
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Summary: | The 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 complementaritydetermining regions (CDRs) classify ∼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 (LCs), 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 (IGLV3-21R110), we show that IGLV3-21R110–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 standalone 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 IGLV3-21R110–expressing CLL cases regardless of IGHV mutational status. Moreover, the generation ofmonoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: P.C.M., S.S., H.V., and H.J. designed research; P.C.M., M.B., M.T.K., M.Y., C.A.M.v.B., V.R., A.N., M.D., E.G.-G., R.S.B., S.F.S., R.A.L.d.G., J.S.P.V., D.S., C.S., E.T., R.B., A.N.M., W.G.M.K., J.T.v.W., K.I., C.E.B., K.K., A.Z., N.C., V.G., S.S., and H.V. performed research; P.C.M., T. Bittolo, G.d.P., M.D., T. Bakchoul, A.R.S., H.M., P.G., K.S., and H.W. contributed new reagents/analytic tools; P.C.M. analyzed data; and P.C.M. and H.J. wrote the paper. 1S.S., H.V., and H.J. contributed equally to this work. Edited by Michael Reth, University of Freiburg, Freiburg, Germany, and approved January 22, 2020 (received for review August 13, 2019) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1913810117 |