Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia
In: Blood, Jg. 131 (2018-06-28), S. 2929-2942
Online
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Zugriff:
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 antileukemic effect associated with CCND3 downregulation. Moreover, we demonstrated that CCND3 expression is critical for BCP-ALL survival and that overexpression of CCND3 protected BCP-ALL cell lines from growth arrest and apoptosis induced by FOXO1 inactivation. Most importantly, pharmacological inhibition of FOXO1 showed antileukemia 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.
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Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia
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Autor/in / Beteiligte Person: | Wirth, Thomas ; Ushmorov, Alexey ; Debatin, Klaus-Michael ; Demir, Salih ; Eckhoff, SM ; Holzmann, Karlheinz ; Lüder Hinrich Meyer ; Osswald, Clarissa D. ; Wang, Fan ; Maier, Thomas ; Seyfried, Felix ; Gehringer, Franziska ; Enzenmüller, Stefanie |
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Zeitschrift: | Blood, Jg. 131 (2018-06-28), S. 2929-2942 |
Veröffentlichung: | American Society of Hematology, 2018 |
Medientyp: | unknown |
ISSN: | 1528-0020 (print) ; 0006-4971 (print) |
DOI: | 10.1182/blood-2017-10-813576 |
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