title: Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML.
abstract: Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations.
authors.affiliation: Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hirabayashi
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.forename: Jessica
authors.initials: J
authors.lastname: Moetter
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Irith
authors.initials: I
authors.lastname: Baumann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.forename: Eva
authors.initials: E
authors.lastname: Bergstraesser
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D011905:Genes, ras; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors; D017381:Spliceosomes / Q000235:genetics*; D000072668:Splicing Factor U2AF; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors