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Fine tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation

Clarissa D. Osswald, Linka Xie, Hanfeng Guan, Franziska Herrmann, Sarah M. Pick, Marion J. Vogel, Franziska Gehringer, Fong Chun Chan, Christian Steidl, Thomas Wirth and Alexey Ushmorov

Key points

  • FOXO3A expression indicates an abortive PC differentiation state in cHL.

  • Tight regulation of FOXO3A is essential for the cHL oncogenic program.

Abstract

We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin-Reed Sternberg (HRS) cells of cHL at higher levels than in Non-Hodgkin lymphoma (NHL) subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here we show that high FOXO3A levels in cHL reflect a B-cell-differentiation specific pattern. In B cells, FOXO3A expression increases during the process of centroblast (CB) to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center (GC) B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1α. As factors attenuating FOXO3A expression in cHL, we identified MIR155 and constitutive activation of ERK. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL.

  • Submitted July 10, 2017.
  • Accepted February 12, 2018.