Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.
PURPOSE To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene- and microRNA-expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.
Langer
Christian
C
Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University, Suite A434 Starling-Loving Hall, 320 W 10th Avenue, Columbus, OH 43210, USA.
Marcucci
Guido
G
Holland
Kelsi B
KB
Radmacher
Michael D
MD
Maharry
Kati
K
Paschka
Peter
P
Whitman
Susan P
SP
Mrózek
Krzysztof
K
Baldus
Claudia D
CD
Vij
Ravi
R
Powell
Bayard L
BL
Carroll
Andrew J
AJ
Kolitz
Jonathan E
JE
Caligiuri
Michael A
MA
Larson
Richard A
RA
Bloomfield
Clara D
CD
D000293:Adolescent; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D016162:Genes, Wilms Tumor; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
C442828:BAALC protein, human; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C072312:ERG protein, human; C497422:KMT2A protein, human; C506524:MN1 protein, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3