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Chronic lymphocytic leukemia

Next-generation IgVH sequencing CLL-like monoclonal B-cell lymphocytosis reveals frequent oligoclonality and ongoing hypermutation

Leukemia volume 30, pages 1055–1061 (2016)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) develops from CLL-like monoclonal B-cell lymphocytosis (MBL) which represents a low-level asymptomatic expansion of cells that phenotypically resemble CLL. Although antigen selection plays a key role during CLL development, it is not known whether this occurs in early MBL or only during progression to CLL. Recent studies suggested that MBL sometimes displays oligoclonality, but these used techniques with limited sensitivity and specificity and were not conclusive. In this study, we combine cell sorting and next-generation sequencing of rearranged immunoglobulin heavy chain variable (IgVH) genes to thoroughly assess the VH repertoire and oligoclonality of purified MBL cells. Clonal functional rearrangements or clonotypes were identified in 29 of 30 sequenced cases, with 7 or 24% having two clonotypes with unrelated CDR3 sequences. In four of the seven cases with unrelated clonotypes, VH segments from the same family were used. In addition, 6 of 29 cases showed clear evidence of ongoing VH gene hypermutation with three of these being among the seven with unrelated clonotypes. This study conclusively shows that MBL cases often contain multiple B-cell clones, the first to report ongoing VH gene mutation in MBL, and that antigen selection appears to occur in early MBL.

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Acknowledgements

This work was supported by the ARUP Institute of Pathology and Sequenta Inc.

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Authors and Affiliations

  1. Sequenta, Inc., South San Francisco, CA, USA

    M Klinger, J Zheng & M Faham

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    K S J Elenitoba-Johnson

  3. Department of Pathology, ARUP Laboratories, University of Utah, Salt Lake City, UT, USA

    S L Perkins & D W Bahler

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  1. M Klinger
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  2. J Zheng
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  4. S L Perkins
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Correspondence to D W Bahler.

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MF is an employee and holder of equity in Sequenta, Inc. The remaining authors declare no conflict of interest.

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Klinger, M., Zheng, J., Elenitoba-Johnson, K. et al. Next-generation IgVH sequencing CLL-like monoclonal B-cell lymphocytosis reveals frequent oligoclonality and ongoing hypermutation. Leukemia 30, 1055–1061 (2016). https://doi.org/10.1038/leu.2015.351

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