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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.

In follicular lymphoma, the t(14;18) status of the peripheral blood and bone marrow analyzed by polymerase chain reaction (PCR) is assumed to correlate with disease activity in patients with relapsed disease. The clinical significance of quantitating circulating lymphoma cells by real-time PCR is reported in patients on first-line treatment. Thirty-four consecutive patients with previously untreated follicular lymphoma and detectable t(14;18)-positive cells in pretreatment peripheral blood samples were monitored. All patients were treated with standard chemotherapy in combination with interferon alfa-2b. Before and after induction therapy, blood samples were taken for quantitative analysis of t(14;18). At presentation, a median of 262 t(14;18)-positive cells per 75,000 normal cells was found (range, 1-75 000). Patients with lower numbers of circulating tumor cells more frequently had bulky disease (P =.02). Seventy-nine percent of the patients responded clinically to treatment. In 22 of 28 patients, including 4 patients in whom treatment had failed clinically, the number of circulating t(14;18)-positive cells decreased to undetectable or low levels after therapy. In the remaining responding patients, circulating tumor cells persisted after therapy. These quantitative data on circulating t(14;18)-positive cells call into question the usefulness of molecular monitoring of the blood in a group of patients with follicular lymphoma uniformly treated with a noncurative first-line regimen. T(14;18)-positive cells decreased in peripheral blood after treatment, irrespective of the clinical response. Therefore, the significance of so-called molecular remission should be reconsidered in follicular lymphoma. (Blood. 2001;98:940-944)