BCL6 corepressor gene dysregulation due to chromosomal translocation in acute myeloid leukemia: a new mechanism based on long non-coding RNA dislocation?

Abstract

Acute myeloid leukemia (AML) is a hematologic disease with heterogeneous clinical and biological features. Although 40 – 50% of patients with AML carry an apparently normal karyotype (NK-AML), several molecular lesions have been found to be associated with this entity, thus improving stratifi cation of patients with NK-AML into prognostic risk groups [1]. Recent studies of cases of NK-AML by next-generation sequencing technologies have led to the identifi cation of new recurrent mutations in the BCL6 corepressor ( BCOR ) gene [2]. Th is gene is located on chromosome Xp11.4 and encodes a transcriptional corepressor with a nuclear localization. BCOR is a pivotal transcriptional regulator of early embryonic development, mesenchymal stem cell function and hemopoiesis [3]. Constitutional inactivating mutations of BCOR have been reported in the oculo-facial-cardiodental (OFCD) syndrome, which has an X-linked inheritance pattern [4]. In NK-AML, BCOR mutations occur in 4% of patients, being distributed along the whole coding sequence, associated with decreased transcript levels, absence of the full-length protein, and lacking/low expression of a truncated BCOR protein [2]. Moreover, the mutations target the functional allele in both male and female patients with AML. Th ese fi ndings support a role played by BCOR as a tumor-suppressor gene, inactivated by mutations in a subset of AML. Moreover, the detection of BCOR mutations seems to confer a poorer prognosis in terms of overall and event-free survival. Recently, BCOR mutations have been described in 4.2% of 354 and in 7.4% of 54 patients aff ected by myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), respectively [5]. Patients with MDS with truncating mutations of BCOR had an inferior overall survival and a higher cumulative incidence of AML transformation [5]. We describe a case of AML with t(X;3) (p11.4;q22.1) showing down-regulated BCOR gene expression. Our fi ndings disclose a novel mechanism for BCOR gene inactivation, unlike those previously reported based on gene point mutations.