TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients

Blood. 2014 Oct 23;124(17):2705-12. doi: 10.1182/blood-2014-06-582809. Epub 2014 Sep 15.

Abstract

Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Azacitidine / analogs & derivatives
  • Azacitidine / therapeutic use
  • Biomarkers, Tumor / genetics
  • Bone Marrow Transplantation / methods
  • DNA Methylation / drug effects*
  • DNA Modification Methylases / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • Decitabine
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Kaplan-Meier Estimate
  • Logistic Models
  • Male
  • Mice, Knockout
  • Mutation*
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Repressor Proteins / genetics
  • Transplantation Chimera / genetics
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • ASXL1 protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • TET2 protein, human
  • Tumor Suppressor Protein p53
  • Decitabine
  • DNA Modification Methylases
  • Azacitidine