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

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, John C. Byrd, L. Jeffrey Medeiros, Steven L. Kunkel, David W. Bahler, Megan S. Lim () and Kojo S. J. Elenitoba-Johnson ()
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Mark J. Kiel: University of Michigan Medical School
Anagh A. Sahasrabuddhe: University of Michigan Medical School
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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9470

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