Let's give BACH2 a breath of fresh air

In this issue of Blood, Zhang and colleagues identify that BACH2 acts as a tumor suppressor protein in mantle cell lymphoma (MCL). Low levels of BACH2 are associated with poor outcome in MCL patients and in vitro resistance in cell lines to both targeted agents (proteasome inhibitor bortezomib, Bruton tyrosine kinase inhibitor ibrutinib) and chemotherapy agents (etoposide, methotrexate). BACH2 is negatively regulated in hypoxic conditions, as in the bone marrow microenvironment, via a regulatory loop involving hypoxia-induced factor-1α, heme, and prolyl hydroxylase 3.¹ 

BACH2 is a transcription factor expressed in B cells from the pro-B cells to mature B cells and is downregulated during the maturation to plasma cells.^2,3  At the common lymphoid progenitor stage, BACH2 represses the myeloid program, pushing cells toward the B-cell development.²  At the pre–B-cell stage, BACH2 competes with BCL6 for binding to promoters of genes coding for checkpoint regulators such as TP53 or CDKN2A, causing the negative selection of pre–B cells not bearing functional VDJ rearrangements.⁴  At later maturation stages, BACH2 cooperates with BCL6, blocking the differentiation to plasma cells, suppressing BLIMP1 expression, and allowing the somatic hypermutation and class switch recombination to take place.⁵  Because of its important role at different maturation stages, it is not surprising that BACH2 is deregulated in neoplastic conditions. The BACH2 gene locus is recurrently deleted in B-cell tumors,⁴  and, similarly to what is reported now in MCL, patients with low BACH2 expression in tumor cells have often been found to have a worse outcome than the remaining patients with higher expression.^4,5 

The activity BACH2 in normal cells is tightly regulated at different levels in a very dynamic way (see figure).⁵  Based on its pattern of expression across B cells, BACH2 is regulated at the transcription level, and the transcription factor PAX5 is a positive regulator.^2,3  However, there are numerous examples of how BACH2 is regulated at the protein level. BCL6 maintains BACH2 protein stability in diffuse large B-cell lymphoma cells and in germinal center B cells, their normal counterparts.³  Heme regulates BACH2 at the protein level, both reducing its stability and decreasing its binding to DNA.^5-7  PI3K/AKT/mTOR-mediated phosphorylation of BACH2 leads to a decreased protein activity, changing its cellular localization from the nucleus to the cytoplasm.⁵  Finally, the production of reactive oxygen species (ROS), for example, induced by cytotoxic drugs such as etoposide, doxorubicin, or cytarabine, determines nuclear localization and activation of BACH2, necessary for the drug-induced cell death.⁸ 

Now, Zhang and colleagues have given BACH2 a breath of fresh air (more specifically, oxygen), studying its role in MCL, but their results also highlight the complexity of the mechanism controlling BACH2 activity, a topic certainly requiring further work.

Do the findings in MCL apply to other lymphomas or leukemias as well? For example, based on 2 MCL cell lines, BACH2 is important for the antitumor response to methotrexate, whereas it seems not necessary in 1 Burkitt lymphoma cell line, in which only drugs inducing ROS benefit from high levels of BACH2.⁸  What is indeed the relationship, if any, between BACH2, hypoxia, and ROS in MCL because, in other systems, ROS are upregulated in hypoxia. Because the interaction of BACH2 with additional transcription factors is fundamental in determining the effect on the transcriptome, it will be important to assess these cofactors in MCL. SOX11 is a transcription factor acting as an oncogene in MCL, positively regulating PAX5 and silencing BLIMP1.⁹  Do BACH2 and SOX11 interact and cooperate? Do the 2 transcription factors share common target genes?

What are the possible clinical consequences of the study for patients affected by MCL? The function of BACH2 expression level as prognostic factor and, in particular, as biomarker of sensitivity to individual anti-cancer agents will have to be prospectively evaluated.