FoxO3 suppresses Myc-driven lymphomagenesis

Abstract

This study demonstrates, for the first time, that loss of a single forkhead box class O (FoxO) transcription factor, can promote lymphomagenesis. Using two different mouse models, we show that FoxO3 has a significant tumour-suppressor function in the context of Myc-driven lymphomagenesis. Loss of FoxO3 significantly accelerated myeloid tumorigenesis in vavP-MYC10 transgenic mice and B lymphomagenesis in Eμ-myc transgenic mice. Tumour analysis indicated that the selective pressure for mutation of the p53 pathway during Eμ-myc lymphomagenesis was not altered. Frank tumours were preceded by elevated macrophage numbers in FoxO3-/- vavP-MYC10 mice but, surprisingly, pre-B-cell numbers were relatively normal in healthy young FoxO3-/- Eμ-myc mice. In vitro assays revealed enhanced survival capacity of Myc-driven cells lacking FoxO3, but no change in cell cycling was detected. The loss of FoxO3 may also be affecting other tumour-suppressive functions for which FoxO1/4 cannot fully compensate.