title: Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event.
abstract: To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V(+) indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1-4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V(+) single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V(-). These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD,
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jawhar
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schwaab
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: Department of Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Department of Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: H-P
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Metzgeroth
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Müller
authors.affiliation: Department of Clinical Chemistry, University Hospital Mannheim, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Naumann
authors.affiliation: Department of Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Walz
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Division of Hematology and Ludwig Boltzmann Cluster Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: W-K
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: 1] Wessex Regional Genetics Laboratory, Salisbury, UK [2] Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fabarius
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reiter
mesh_terms: D000368:Aged; D019070:Cell Lineage; D002469:Cell Separation; D003582:Cytogenetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008407:Mast Cells / Q000166:cytology; D034721:Mastocytosis, Systemic / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D013234:Stem Cells / Q000166:cytology*
chemical_list: C473949:ASXL1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human; D019009:Proto-Oncogene Proteins c-kit