title: The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia.
abstract: T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells are intriguing entities between benign and malignant lymphoproliferation. The molecular pathogenesis has partly been uncovered by the recent discovery of somatic activating STAT3 and STAT5b mutations. Here we show that 43% (75/174) of patients with T-cell large granular lymphocytic leukemia and 18% (7/39) with chronic lymphoproliferative disorder of natural killer cells harbor STAT3 mutations when analyzed by quantitative deep amplicon sequencing. Surprisingly, 17% of the STAT3-mutated patients carried multiple STAT3 mutations, which were located in different lymphocyte clones. The size of the mutated clone correlated well with the degree of clonal expansion of the T-cell repertoire analyzed by T-cell receptor beta chain deep sequencing. The analysis of sequential samples suggested that current immunosuppressive therapy is not able to reduce the level of the mutated clone in most cases, thus warranting the search for novel targeted therapies. Our findings imply that the clonal landscape of large granular lymphocytic leukemia is more complex than considered before, and a substantial number of patients have multiple lymphocyte subclones harboring different STAT3 mutations, thus mimicking the situation in acute leukemia.
authors.affiliation: Hematology Research Unit, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: Hanna L M
authors.initials: HL
authors.lastname: Rajala
authors.affiliation: University of Virginia Cancer Center, Charlottesville, VA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Olson
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Finland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lagström
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.affiliation: Department of Clinical Chemistry and TYKSLAB, University of Turku and Turku University Central Hospital, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Lundan
authors.affiliation: Adaptive Biotechnologies Corp, Seattle, WA, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hamm
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Finland.
authors.forename: Syed Arshi Uz
authors.initials: SA
authors.lastname: Zaman
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Finland.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Lopez Marti
authors.affiliation: Hematology Research Unit, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: Emma I
authors.initials: EI
authors.lastname: Andersson
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.affiliation: Hematology Research Unit, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: University of Virginia Cancer Center, Charlottesville, VA, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Hematology Research Unit, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland satu.mustjoki@helsinki.fi.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis*; D060965:Clonal Evolution / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050796:STAT3 Transcription Factor