title: KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance.
abstract: Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 μg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of ≥2 × 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Schwaab
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Umbach
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Metzgeroth
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Naumann
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Jawhar
authors.affiliation: Department of Pathology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Department of Pathology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Department of Pathology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: MLL, Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury District Hospital, Salisbury, United Kingdom.|Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Fabarius
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001201:Ascites / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D015870:Gene Expression; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D053614:Janus Kinase 2 / Q000235:genetics*; D008206:Lymphatic Diseases / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012008:Recurrence; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D012737:Sex Factors; D016019:Survival Analysis; D053802:Tryptases / Q000097:blood; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012261:Ribonucleoproteins; D039221:mRNA Cleavage and Polyadenylation Factors; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human; C479819:FIP1L1-PDGFRA fusion protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053802:Tryptases