title: Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling.
abstract: Mutations in splice factor (SF) genes occur more frequently in myelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bone marrow of 47 refractory anemia with excess blasts (RAEB) patients, 29 AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SF-hotspot mutations in SF3B1, U2AF35, and SRSF2. SF mutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewide messenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient cluster with an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival. We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups. We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.
authors.affiliation: Department of Hematology, and.
authors.forename: Erdogan
authors.initials: E
authors.lastname: Taskesen
authors.affiliation: Department of Hematology, and.
authors.forename: Marije
authors.initials: M
authors.lastname: Havermans
authors.affiliation: Department of Hematology, and.
authors.forename: Kirsten
authors.initials: K
authors.lastname: van Lom
authors.affiliation: Department of Hematology, and.
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Clinical Trial Center, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Norden
authors.affiliation: Department of Hematology, and.
authors.forename: Eric
authors.initials: E
authors.lastname: Bindels
authors.affiliation: Department of Hematology, and.
authors.forename: Remco
authors.initials: R
authors.lastname: Hoogenboezem
authors.affiliation: Delft Bioinformatics Laboratory, Delft University of Technology, Delft, The Netherlands; Netherlands Bioinformatics Centre, Nijmegen, The Netherlands;
authors.forename: Marcel J T
authors.initials: MJ
authors.lastname: Reinders
authors.affiliation: University of Michigan, Ann Arbor, MI; and.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.affiliation: Department of Hematology, and.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.affiliation: Department of Hematology, and.
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Department of Medicine, Hematology Oncology Division, Cornell, NY.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Department of Hematology, and Clinical Trial Center, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics; D016172:DNA Fingerprinting; D019175:DNA Methylation; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D000072668:Splicing Factor U2AF
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