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

George S. Laszlo, Todd A. Alonzo, Chelsea J. Gudgeon, Kimberly H. Harrington, Alex Kentsis, Robert B. Gerbing, Yi Cheng Wang, Rhonda E. Ries, Susana C. Raimondi, Betsy A. Hirsch, Alan S. Gamis, Soheil Meshinchi, Roland B. Walter

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Article number115
JournalJournal of Hematology and Oncology
Volume8
Issue number1
DOIs
StatePublished - Oct 20 2015

Keywords

  • AAML0531
  • Acute myeloid leukemia (AML)
  • Adverse risk
  • Biomarker
  • Children's Oncology Group (COG)
  • Myocyte enhancer factor 2C (MEF2C)
  • Pediatric
  • Transcription factor

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