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Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK–STAT pathway in Sézary syndrome

Author

Listed:
  • Mark J. Kiel

    (University of Michigan Medical School)

  • Anagh A. Sahasrabuddhe

    (University of Michigan Medical School
    Present address: Department of Biotechnology, Pandit Ravishankar Shukla University, Raipur, India.)

  • Delphine C. M. Rolland

    (Perelman School of Medicine at University of Pennsylvania)

  • Thirunavukkarasu Velusamy

    (University of Michigan Medical School)

  • Fuzon Chung

    (University of Michigan Medical School)

  • Matthew Schaller

    (University of Michigan Medical School)

  • Nathanael G. Bailey

    (University of Michigan Medical School)

  • Bryan L. Betz

    (University of Michigan Medical School)

  • Roberto N. Miranda

    (The University of Texas MD Anderson Cancer Center)

  • Pierluigi Porcu

    (The Ohio State University)

  • John C. Byrd

    (The Ohio State University)

  • L. Jeffrey Medeiros

    (The University of Texas MD Anderson Cancer Center)

  • Steven L. Kunkel

    (University of Michigan Medical School)

  • David W. Bahler

    (The University of Utah Health Sciences Center)

  • Megan S. Lim

    (Perelman School of Medicine at University of Pennsylvania)

  • Kojo S. J. Elenitoba-Johnson

    (Perelman School of Medicine at University of Pennsylvania
    Center for Personalized Diagnostics, Perelman School of Medicine at University of Pennsylvania.)

Abstract

Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.

Suggested Citation

  • Mark J. Kiel & Anagh A. Sahasrabuddhe & Delphine C. M. Rolland & Thirunavukkarasu Velusamy & Fuzon Chung & Matthew Schaller & Nathanael G. Bailey & Bryan L. Betz & Roberto N. Miranda & Pierluigi Porcu, 2015. "Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK–STAT pathway in Sézary syndrome," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9470
    DOI: 10.1038/ncomms9470
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