High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study.
OBJECTIVE
To validate ERG overexpression as an adverse predictor and assess its prognostic value in the context of other molecular markers in cytogenetically normal (CN) -acute myeloid leukemia (AML).


METHODS
Seventy-six adult patients with primary CN-AML, younger than 60 years and treated on Cancer and Leukemia Group B (CALGB) trial 19808, were evaluated for ERG expression by quantitative reverse transcriptase polymerase chain reaction. They were then combined with 72 patients enrolled onto CALGB 9621 for analyses that included other molecular markers.


RESULTS
Similar to patients enrolled onto CALGB 9621, high ERG expressers on CALGB 19808 had fewer complete remissions (CRs; P = .03) and worse event-free survival (EFS; P = .016) than low ERG expressers. In the combined set, high expressers (n = 55) had fewer CRs (P = .004) and shorter EFS (P < .001) than low expressers (n = 93). High ERG predicted failure to achieve CR (P = .004) after adjusting for BAALC expression (P = .04) and age (P = .008), and EFS (P = .004) after adjusting for FLT3 internal tandem duplication (ITD; P < .001). Among patients without FLT3-ITD (FLT3-ITD negative), only high ERG predicted shorter EFS (P = .001). Among NPM1-mutated (NPM1 positive) patients, high ERG predicted shorter EFS (P = .003), after adjusting for FLT3-ITD (P < .001). When all three markers were considered together, in the favorable FLT3-ITD-negative/NPM1-positive subset, high ERG was the only factor predicting shorter EFS (P = .002).


CONCLUSIONS
We validated ERG overexpression as an adverse predictor in CN-AML. Moreover, by using ERG expression levels, we improved the previously proposed molecular-risk classification of CN-AML based on the presence or absence of FLT3-ITD and NPM1 mutations, given that we identified subsets with different outcome among FLT3-ITD-negative, NPM1-positive, and FLT3-ITD-negative/NPM1-positive patients.
Marcucci
Guido
G
Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. guido.marcucci@osumc.edu
Maharry
Kati
K
Whitman
Susan P
SP
Vukosavljevic
Tamara
T
Paschka
Peter
P
Langer
Christian
C
Mrózek
Krzysztof
K
Baldus
Claudia D
CD
Carroll
Andrew J
AJ
Powell
Bayard L
BL
Kolitz
Jonathan E
JE
Larson
Richard A
RA
Bloomfield
Clara D
CD
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C072312:ERG protein, human; C000716967:NPM1 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D000090243:Nucleophosmin