Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia

Blood. 2014 Aug 28;124(9):1513-21. doi: 10.1182/blood-2014-03-560227. Epub 2014 Jun 26.


Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Cycle Proteins / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Cohort Studies
  • Core Binding Factor Alpha 2 Subunit / genetics
  • DNA Methylation / genetics
  • Female
  • Genes, ras
  • Genetic Association Studies
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Myelodysplastic Syndromes / classification
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / pathology
  • Myelodysplastic-Myeloproliferative Diseases / classification
  • Myelodysplastic-Myeloproliferative Diseases / genetics*
  • Myelodysplastic-Myeloproliferative Diseases / pathology
  • Myeloid Cells / pathology
  • Phosphoproteins / genetics
  • Prognosis
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Core Binding Factor Alpha 2 Subunit
  • Phosphoproteins
  • RNA Splicing Factors
  • RUNX1 protein, human
  • Ribonucleoprotein, U2 Small Nuclear
  • SF3B1 protein, human
  • cohesins