High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse-risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group

J Hematol Oncol. 2015 Oct 20:8:115. doi: 10.1186/s13045-015-0215-4.

Abstract

Background: Recent studies have identified myocyte enhancer factor 2C (MEF2C) as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML, raising the possibility that MEF2C could serve as marker of poor-risk AML and, therefore, have prognostic significance.

Methods: To test this hypothesis, we retrospectively quantified MEF2C expression in pretreatment bone marrow specimens in participants of the AAML0531 trial by reverse-transcriptase polymerase chain reaction and correlated expression levels with disease characteristics and clinical outcome.

Results: In all 751 available patient specimens, MEF2C messenger RNA (mRNA) was detectable and varied >3000-fold relative to β-glucuronidase. Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67 vs. 78 %, P = 0.005). They also had an inferior overall survival (P = 0.014; at 5 years 55 ± 8 vs. 67 ± 4 %), inferior event-free survival (P < 0.001; at 5 years 38 ± 7 vs. 54 ± 4 %), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P < 0.001; at 5 years 53 ± 9 vs. 35 ± 5 %). These differences were accounted for by lower prevalence of cytogenetically/molecularly defined low-risk disease (16 vs. 46 %, P < 0.001) and higher prevalence of standard-risk disease (68 vs. 42 %, P < 0.001) in patients with high MEF2C expression, suggesting that MEF2C cooperates with additional pathogenic abnormalities.

Conclusions: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. With confirmation that high MEF2C mRNA expression leads to overexpression of MEF2C protein, these findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aminoglycosides / adverse effects
  • Aminoglycosides / therapeutic use*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Child
  • Child, Preschool
  • Female
  • Gemtuzumab
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / metabolism
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Male
  • Multivariate Analysis
  • Prognosis
  • Regression Analysis
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

Substances

  • Aminoglycosides
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • MEF2 Transcription Factors
  • MEF2C protein, human
  • Gemtuzumab