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Molecular targets for therapy

Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome

Leukemia volume 31, pages 170–176 (2017)Cite this article

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Abstract

High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2–4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

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Acknowledgements

This work was supported by the Henry Predolin Foundation and NIH grant CA197120.

Author contributions

SB, JO, CS, KMK, SP and EB performed the experiments; SB, KGC, SLS and EB analyzed the results; SB, TDS, DLV, RF, SLS, NEK and EB designed the research; SB and EB wrote the paper.

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Authors and Affiliations

  1. Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA

    S Barrio, J Ojha, K M Kortüm, S Pathangey, R Fonseca & E Braggio

  2. Department of Medicine, Mayo Clinic, Rochester, MN, USA

    T D Shanafelt, C Secreto & N E Kay

  3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    K G Chaffee & S L Slager

  4. Department of Hematology, University Hospital, Würzburg, Germany

    K M Kortüm

  5. Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    D L Van-Dyke

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  1. S Barrio
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Correspondence to E Braggio.

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Competing interests

RF has received a patent for the prognostication of MM based on genetic categorization of the disease. He has received consulting fees from Celgene, Genzyme, BMS, Bayer, Lilly, Onyx, Binding Site, Novartis, Sanofi, Millennium and AMGEN. He also has sponsored research from Onyx. He is also a member of the Scientific Advisory Board of Applied Biosciences.

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Barrio, S., Shanafelt, T., Ojha, J. et al. Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome. Leukemia 31, 170–176 (2017). https://doi.org/10.1038/leu.2016.172

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