title: Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia.
abstract: Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin.
authors: Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Sarah Abu
authors: SA
authors: Kar
authors: Anna
authors: A
authors: Jankowska
authors: Hideki
authors: H
authors: Makishima
authors: Valeria
authors: V
authors: Visconte
authors: Andres
authors: A
authors: Jerez
authors: Yuka
authors: Y
authors: Sugimoto
authors: Hideki
authors: H
authors: Muramatsu
authors: Fabiola
authors: F
authors: Traina
authors: Manuel
authors: M
authors: Afable
authors: Kathryn
authors: K
authors: Guinta
authors: Ramon V
authors: RV
authors: Tiu
authors: Bartlomiej
authors: B
authors: Przychodzen
authors: Hirotoshi
authors: H
authors: Sakaguchi
authors: Seiji
authors: S
authors: Kojima
authors: Mikkael A
authors: MA
authors: Sekeres
authors: Alan F
authors: AF
authors: List
authors: Michael A
authors: MA
authors: McDevitt
authors: Jaroslaw P
authors: JP
authors: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis / Q000235:genetics*; D054429:Leukemia, Myelomonocytic, Juvenile / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics*