The BCL6-IRF4-BLIMP1 transcription factor axis as a therapeutic target in T-cell lymphoma

Abstract

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of clinically aggressive malignancies derived from mature (post-thymic) T-cells or Natural Killer cells, which comprise approximately 10-15% of all non-Hodgkin lymphomas. In contrast to aggressive B-cell malignancies, which are often curable and for which advances in understanding disease biology have resulted in new targeted treatment approaches, the treatment of PTCL remains inadequate. Apart from those with ALK-positive anaplastic large cell lymphoma (ALCL), patients presenting with PTCL have a poor outcome with only approximately 25% cured of their disease. The pathogenesis of T-cell lymphoma is poorly understood and few new targeted therapies are emerging. The transcription factors BCL6, IRF4 and BLIMP1 function in a regulatory network to direct mature B-cell differentiation. They are genetically altered and dysregulated in B-cell malignancy, and BCL6 and IRF4 represent potential therapeutic targets. These transcription factors also interact to regulate T-cell differentiation and emerging data indicated genetic alteration in some PTCL. This project investigated the importance of BCL6, IRF4, and BLIMP1 in the regulation of PTCL cell line proliferation and survival using ALCL cell lines in vitro as a model. Lentiviral-mediated knockdown of BCL6 and IRF4, and overexpression of BLIMP1, each resulted in reduced proliferation / survival of some, but not all, ALCL cell lines tested, and no clear pattern of response emerged. These effects were associated with small changes in cell cycle progression and induction of apoptosis. Modulation of each of the transcription factors had small effects on the expression of the others, again with variable patterns between cell lines. IRF4 knockdown revealed a positive interaction with c-MYC a􀅶d BLIMP􀏭α i􀅶 􀏮/􀏯 ALK+ ALCL cell lines. Intriguingly, ALK inhibition with crizotinib revealed different patterns of NPM-ALK mediated dysregulation of the transcription factors across the cell lines. These data support a positive role for BCL6 and IRF4 in the maintenance of ALCL, and an inhibitory / tumour suppressor role for BLIMP1, but show variability in dependencies between cell lines which could reflect clinically important disease heterogeneity which must be considered when targeting this transcription factor axis therapeutically.