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Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Author

Listed:
  • Jan A. Burger

    (MD Anderson Cancer Center)

  • Dan A. Landau

    (Broad Institute
    Weill Cornell Medicine
    Weill Cornell Medicine
    New York Genome Center)

  • Amaro Taylor-Weiner

    (Broad Institute)

  • Ivana Bozic

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University)

  • Huidan Zhang

    (School of Engineering and Applied Sciences, Harvard University
    Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University
    Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China)

  • Kristopher Sarosiek

    (Dana-Farber Cancer Institute)

  • Lili Wang

    (Dana-Farber Cancer Institute)

  • Chip Stewart

    (Broad Institute)

  • Jean Fan

    (Center for Biomedical Informatics, Harvard Medical School)

  • Julia Hoellenriegel

    (MD Anderson Cancer Center)

  • Mariela Sivina

    (MD Anderson Cancer Center)

  • Adrian M. Dubuc

    (Brigham and Women's Hospital and Harvard Medical School)

  • Cameron Fraser

    (Dana-Farber Cancer Institute)

  • Yulong Han

    (Bioinspired Engineering and Biomechanics Center, Xi’an Jiaotong University)

  • Shuqiang Li

    (Fluidigm Corporation)

  • Kenneth J. Livak

    (Fluidigm Corporation)

  • Lihua Zou

    (Broad Institute)

  • Youzhong Wan

    (Dana-Farber Cancer Institute)

  • Sergej Konoplev

    (MD Anderson Cancer Center)

  • Carrie Sougnez

    (Broad Institute)

  • Jennifer R. Brown

    (Dana-Farber Cancer Institute)

  • Lynne V. Abruzzo

    (MD Anderson Cancer Center)

  • Scott L. Carter

    (Broad Institute)

  • Michael J. Keating

    (MD Anderson Cancer Center)

  • Matthew S. Davids

    (Dana-Farber Cancer Institute)

  • William G. Wierda

    (MD Anderson Cancer Center)

  • Kristian Cibulskis

    (Broad Institute)

  • Thorsten Zenz

    (National Center for Tumors and German Cancer Research Center (DKFZ))

  • Lillian Werner

    (Biostatistics and Computational Biology, Dana-Farber Cancer Institute)

  • Paola Dal Cin

    (Brigham and Women's Hospital and Harvard Medical School)

  • Peter Kharchencko

    (Center for Biomedical Informatics, Harvard Medical School)

  • Donna Neuberg

    (Biostatistics and Computational Biology, Dana-Farber Cancer Institute)

  • Hagop Kantarjian

    (MD Anderson Cancer Center)

  • Eric Lander

    (Broad Institute)

  • Stacey Gabriel

    (Broad Institute)

  • Susan O’Brien

    (MD Anderson Cancer Center)

  • Anthony Letai

    (Dana-Farber Cancer Institute)

  • David A. Weitz

    (School of Engineering and Applied Sciences, Harvard University)

  • Martin A. Nowak

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University)

  • Gad Getz

    (Broad Institute)

  • Catherine J. Wu

    (Broad Institute
    Dana-Farber Cancer Institute
    Brigham & Women's Hospital, Harvard Medical School)

Abstract

Resistance to the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

Suggested Citation

  • Jan A. Burger & Dan A. Landau & Amaro Taylor-Weiner & Ivana Bozic & Huidan Zhang & Kristopher Sarosiek & Lili Wang & Chip Stewart & Jean Fan & Julia Hoellenriegel & Mariela Sivina & Adrian M. Dubuc & , 2016. "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11589
    DOI: 10.1038/ncomms11589
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    Cited by:

    1. Benjamin Wölfl & Hedy te Rietmole & Monica Salvioli & Artem Kaznatcheev & Frank Thuijsman & Joel S. Brown & Boudewijn Burgering & Kateřina Staňková, 2022. "The Contribution of Evolutionary Game Theory to Understanding and Treating Cancer," Dynamic Games and Applications, Springer, vol. 12(2), pages 313-342, June.
    2. Martin F. M. Rooij & Yvonne J. Thus & Nathalie Swier & Roderick L. Beijersbergen & Steven T. Pals & Marcel Spaargaren, 2022. "A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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