High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9–positive patients

• Published in: Blood 2011-11, Vol.118 (20), p.5613-5621
• Main Authors: Noordermeer, Sylvie M., Sanders, Mathijs A., Gilissen, Christian, Tönnissen, Evelyn, van der Heijden, Adrian, Döhner, Konstanze, Bullinger, Lars, Jansen, Joop H., Valk, Peter J.M., van der Reijden, Bert A.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cohort Studies; Databases, Factual; Gene Expression Profiling; Genetic Testing - methods; Genetic Testing - standards; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes - cytology; Medical sciences; Myeloid-Lymphoid Leukemia Protein - genetics; Nerve Tissue Proteins - genetics; Oncogene Proteins, Fusion - genetics; Predictive Value of Tests; Prognosis; Reproducibility of Results; Risk Factors; Treatment Outcome; Ubiquitination - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-06-359182

Aberrations in protein ubiquitination have recently been identified in the pathogenesis of acute myeloid leukemia (AML). We studied whether expression changes of more than 1600 ubiquitination related genes correlated with clinical outcome in 525 adult AML patients. High expression of one of these genes, BRE, was observed in 3% of the cases and predicted favorable prognosis independently of known prognostic factors (5-year overall survival: 57%). Remarkably, unsupervised expression profiling showed that 86% of high BRE-expressing patients were confined to a previously unrecognized cluster. High BRE expression was mutually exclusive with FLT3 ITD, CEBPA, IDH1, and IDH2 mutations, EVI1 overexpression, and favorable karyotypes. In contrast, high BRE expression co-occurred strongly with FAB M5 morphology and MLL-AF9 fusions. Within the group of MLL-AF9–positive patients, high BRE expression predicted superior survival, while normal BRE expression predicted extremely poor survival (5-year overall survival of 80% vs 0%, respectively, P = .0002). Both the co-occurrence of high BRE expression with MLL-AF9 and its prognostic impact were confirmed in an independent cohort of 436 AML patients. Thus, high BRE expression defines a novel subtype of adult AML characterized by a favorable prognosis. This work contributes to improved risk stratification in AML, especially among MLL-AF9–positive patients.