title: Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1.
abstract: OBJECTIVE
  Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that is characterized by features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. Thus far, data on a comprehensive cytogenetic or molecular genetic characterization are limited.
  
  
  METHODS
  Here, we analyzed 81 thoroughly characterized patients with CMML (CMML type 1, n = 45; CMML type 2, n = 36) by applying next-generation sequencing (NGS) technology to investigate CBL, JAK2, MPL, NRAS, and KRAS at known mutational hotspot regions. In addition, complete coding regions were analyzed for RUNX1 (beta isoform) and TET2 aberrations.
  
  
  RESULTS
  Cytogenetic aberrations were found in 18.2% of patients (14 of 77 patients). In contrast, at least one molecular mutation was observed in 72.8% of patients (59 of 81 patients). A mean of 1.6 mutations per patient was observed by this unprecedented screening. In total, 105 variances were detected by this comprehensive molecular screening. After excluding known polymorphisms or silent mutations, 82 distinct mutations remained (CBL, n = 15; JAK2V617F, n = 8; MPL, n = 0; NRAS, n = 10; KRAS, n = 12; RUNX1, n = 7; and TET2, n = 41). With respect to clinical data, a better outcome was seen for patients carrying TET2 mutations (P = .013).
  
  
  CONCLUSIONS
  The number of molecular markers used to categorize myeloid neoplasms is constantly increasing. Here, NGS screening has been demonstrated to support a comprehensive characterization of the molecular background in CMML. A pattern of molecular mutations translates into different biologic and prognostic categories of CMML.
authors.affiliation: MLL Munich Leukemia Laboratory, München, Germany. alexander.kohlmann@mll-online.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Vera
authors.initials: V
authors.lastname: Grossmann
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Sonja
authors.initials: S
authors.lastname: Schindela
authors.forename: Tamara
authors.initials: T
authors.lastname: Weiss
authors.forename: Beray
authors.initials: B
authors.lastname: Kazak
authors.forename: Frank
authors.initials: F
authors.lastname: Dicker
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
mesh_terms: D000328:Adult; D000368:Aged; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D011905:Genes, ras; D006801:Humans; D053208:Kaplan-Meier Estimate; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D018631:ras Proteins; C067419:CBL protein, human