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.
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.



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.



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.



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.
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.
George S
GS
Laszlo
Department of Biostatistics, University of Southern California, Los Angeles, CA, USA.|Children's Oncology Group, Monrovia, CA, USA.
Todd A
TA
Alonzo
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.
Chelsea J
CJ
Gudgeon
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.
Kimberly H
KH
Harrington
Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Weill Medical College of Cornell University, New York, NY, USA.
Alex
A
Kentsis
Children's Oncology Group, Monrovia, CA, USA.
Robert B
RB
Gerbing
Children's Oncology Group, Monrovia, CA, USA.
Yi-Cheng
YC
Wang
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.
Rhonda E
RE
Ries
Children's Oncology Group, Monrovia, CA, USA.|Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Susana C
SC
Raimondi
Children's Oncology Group, Monrovia, CA, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota Cancer Center, Minneapolis, MN, USA.
Betsy A
BA
Hirsch
Children's Oncology Group, Monrovia, CA, USA.|Division of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.
Alan S
AS
Gamis
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA.|Children's Oncology Group, Monrovia, CA, USA.|Department of Pediatrics, University of Washington, Seattle, WA, USA.
Soheil
S
Meshinchi
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA, 98109-1024, USA. rwalter@fredhutch.org.|Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA. rwalter@fredhutch.org.|Department of Epidemiology, University of Washington, Seattle, WA, USA. rwalter@fredhutch.org.
Roland B
RB
Walter
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000617:Aminoglycosides / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D000079982:Gemtuzumab; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D012044:Regression Analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D000079982:Gemtuzumab