ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays.
OBJECTIVE
Recently, several novel molecular prognostic markers were identified in cytogenetically normal acute myeloid leukemia (CN-AML). In addition to the well-known influence of FLT3, NPM1, and CEBPA mutations, high transcript levels of the ERG, BAALC, and MN1 genes have been associated with inferior outcomes, but the relative importance of these risk markers remains to be defined.


METHODS
We analyzed ERG, BAALC, and MN1 expression levels in a cohort of 210 patients with CN-AML who received intensive chemotherapy. Expression levels of ERG, BAALC, and MN1 were determined in bone marrow samples by using oligonucleotide microarrays.


RESULTS
High transcript levels of ERG, BAALC, and MN1 were predictors for inferior overall survival (OS) and a lower rate of complete remissions (CRs). There were significant positive correlations between the expression levels of all three genes. ERG expression levels predicted OS in elderly patients (ie, age 60 years or older) with CN-AML (P = .006) as well as in younger patients (P = .013). In multivariate analyses, high ERG expression was independently associated with a lower CR rate (P = .013), shorter event-free survival (P = .008), and shorter OS (P = .005). Patients who had low ERG levels and absent FLT3 internal tandem duplication (ITD) had a 5-year OS of 44%, and patients who had high ERG expression and FLT3 ITD had a 5-year OS of only 5%.


CONCLUSIONS
We analyzed a comprehensive set of molecular risk factors in a large, homogeneous CN-AML patient cohort. In this study, high ERG expression levels emerged as a strong negative prognostic factor and provided prognostic information in addition to established molecular markers.
Metzeler
Klaus H
KH
Department of Internal Medicine III, Institute for Medical Informatics, Biometry, and Epidemiology, University Hospital Grosshadern, Ludwig-Maximilians Universität, München, Germany.
Dufour
Annika
A
Benthaus
Tobias
T
Hummel
Manuela
M
Sauerland
Maria-Cristina
MC
Heinecke
Achim
A
Berdel
Wolfgang E
WE
Büchner
Thomas
T
Wörmann
Bernhard
B
Mansmann
Ulrich
U
Braess
Jan
J
Spiekermann
Karsten
K
Hiddemann
Wolfgang
W
Buske
Christian
C
Bohlander
Stefan K
SK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
C442828:BAALC protein, human; C072312:ERG protein, human; C506524:MN1 protein, human; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin