TitleTwo splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling.
Publication TypeJournal Article
Year of Publication2014
AuthorsTaskesen, Erdogan, Havermans Marije, van Lom Kirsten, Sanders Mathijs A., van Norden Yvette, Bindels Eric, Hoogenboezem Remco, Reinders Marcel J. T., Figueroa Maria E., Valk Peter J. M., Löwenberg Bob, Melnick Ari, and Delwel Ruud
Date Published2014 May 22
KeywordsAdult, Aged, Aged, 80 and over, Anemia, Refractory, with Excess of Blasts, DNA Fingerprinting, DNA Methylation, Female, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Phosphoproteins, Ribonucleoprotein, U2 Small Nuclear, Ribonucleoproteins, RNA Splicing Factors, Serine-Arginine Splicing Factors, Splicing Factor U2AF

<p>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.</p>

Alternate JournalBlood
PubMed ID24668493