title: Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.
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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kiel
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Anagh A
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Delphine C M
authors.initials: DCM
authors.lastname: Rolland
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Velusamy
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Fuzon
authors.initials: F
authors.lastname: Chung
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Nathanael G
authors.identifier: http://orcid.org/0000-0002-6747-680X
authors.initials: NG
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Betz
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Pierluigi
authors.identifier: http://orcid.org/0000-0002-8056-023X
authors.initials: P
authors.lastname: Porcu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.affiliation: Department of Pathology, The University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Bahler
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Center for Personalized Diagnostics, Perelman School of Medicine at University of Pennsylvania., Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kojo S J
authors.initials: KSJ
authors.lastname: Elenitoba-Johnson
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D059472:Exome; D023281:Genomics; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D053612:Janus Kinases / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D019169:Jurkat Cells; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics; D050791:STAT Transcription Factors / Q000235:genetics*; D012751:Sezary Syndrome / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D050791:STAT Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D053612:Janus Kinases; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; D018631:ras Proteins; C426242:CARD11 protein, human; D006162:Guanylate Cyclase