Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

SIMPLE SUMMARY: Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia with a highly variable presentation, clinical course, and outcome. The overall aim of our study was to determine the clinical and functional significance of two B-cell regulators, BACH2 and BCL6, in CLL. The results showed that CLL patients expressing low levels of BACH2 and BCL6 RNA had a shorter overall survival (OS). Their low RNA expression was associated with a shorter overall survival of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Further, co-immunoprecipitation and mass spectrometry studies from MEC-1 CLL cells showed no direct interaction between BACH2 and BCL6, but shared protein networks that are involved in ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology. Taken together, this study reports BACH2 as a potential prognosticator and indicates the protein networks influenced by BCL6 and BACH2 in CLL. ABSTRACT: Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.