Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia
Sarah Abu Kar,
Anna Jankowska,
Hideki Makishima,
Valeria Visconte,
Andres Jerez,
Yuka Sugimoto,
Hideki Muramatsu,
Fabiola Traina,
Manuel Afable,
Kathryn Guinta,
Ramon V. Tiu,
Bartlomiej Przychodzen,
Hirotoshi Sakaguchi,
Seiji Kojima,
Mikkael A. Sekeres,
Alan F. List,
Michael A. McDevitt,
Jaroslaw P. Maciejewski
Affiliations
Sarah Abu Kar
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Anna Jankowska
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Hideki Makishima
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Valeria Visconte
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Andres Jerez
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Yuka Sugimoto
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Hideki Muramatsu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Fabiola Traina
Hematology and Hemotherapy Center, National Institute of Blood, School of Medical Sciences, University of Campinas, Campinas, Brazil
Manuel Afable
Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
Kathryn Guinta
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Ramon V. Tiu
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA;Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
Bartlomiej Przychodzen
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
Hirotoshi Sakaguchi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Seiji Kojima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Mikkael A. Sekeres
Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
Alan F. List
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Michael A. McDevitt
Division of Hematology and Hematological Malignancy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jaroslaw P. Maciejewski
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA;Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
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.
