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Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia

Fan Wang, Salih Demir, Franziska Gehringer, Clarissa D. Osswald, Felix Seyfried, Stefanie Enzenmüller, Sarah M. Eckhoff, Thomas Maier, Karlheinz Holzmann, Klaus-Michael Debatin, Thomas Wirth, Lüder H. Meyer and Alexey Ushmorov

Key points

  • FOXO1 activity is essential for growth and maintenance of B-cell precursor acute lymphoblastic leukemia.

  • Inhibition of FOXO1 reduces leukemia load and prolongs survival in a preclinical model of BCP-ALL.

Abstract

The FOXO1 transcription factor plays an essential role in the regulation of proliferation and survival programs at early stages of B-cell differentiation. Here, we show that tightly-regulated FOXO1 activity is essential for maintenance of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Genetic and pharmacological inactivation of FOXO1 in BCP-ALL cell lines produced a strong anti-leukemic effect associated with CCND3 downregulation. Moreover, we demonstrated that CCND3 expression is critical for BCP-ALL survival and overexpression of CCND3 protected BCP-ALL cell lines from growth arrest and apoptosis induced by FOXO1 inactivation. Most importantly, pharmacologic inhibition of FOXO1 showed anti-leukemia activity on several primary, patient-derived, pediatric ALL xenografts with effective leukemia reduction in the hematopoietic, lymphoid, and central nervous system organ compartments, ultimately leading to prolonged survival without leukemia reoccurrence in a preclinical in vivo model of BCP-ALL. These results suggest that repression of FOXO1 might be a feasible approach for the treatment of BCP-ALL.

  • Submitted October 30, 2017.
  • Accepted March 26, 2018.