In contrast to other B cell lymphomas, Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), have mainly lost their B cell identity. Recently, we reported that the transcription factor FOXO1, indispensable for B cell development and differentiation, is downregulated in HRS cells and expression of FOXO1 results in growth arrest and apoptosis in cHL cell lines.

We found that FOXO1 activation led to downregulation of genes, which are normally upregulated in cHL, such as CD30/TNFRSF8 and the proto-oncogene MYC. On the other hand, FOXO1 activated expression of germinal center-specific genes including BCL6, AICDA, BACH2, and GCET2. The most surprising finding was induction of BLIMP-1/PRDM1, the master regulator of plasma cell differentiation and tumor suppressor in activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). A positive correlation of FOXO1 and BLIMP-1 expression in microdissected HRS cells further indicated a role for FOXO1 in BLIMP-1 regulation. 

Overexpression of BLIMP-1α using a lentiviral vector strongly inhibited growth of cHL cell lines. In line with the fact that BLIMP-1 and MYC form a negative feedback loop, we found that ectopic BLIMP-1α expression resulted in downregulation of MYC protein levels, which most likely contributes to the anti-tumor effect of BLIMP-1α. On the other hand, MYC inhibition in cHL cell lines led to BLIMP-1 upregulation. Thus, our data indicate that FOXO1, BLIMP-1 and MYC constitute a negative feed-forward regulatory loop, which is controlled by FOXO1. 

Taken together, we show for the first time that FOXO1 induces expression of BLIMP-1. We identified BLIMP-1α as a tumor suppressor which downregulates expression of the proto-oncogene MYC in cHL. Therefore, FOXO1 might exert its tumor suppressor function at least in part by upregulation of BLIMP-1α. 

Further work on BLIMP-1α regulation by FOXO1 and investigation of a potential role of FOXO1 in plasma cell differentiation is warranted. 

Peter Möller and Frank Leithäuser, Department of Pathology, University of Ulm, Ulm, Germany

Randy Gascoyne and Christian Steidl. Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancers and the Centre for Translational and Applied Genomics, Vancouver, Canada

Reuben Tooze, Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK