Abstract 2009: Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL)

Abstract

Although treatment of B cell precursor acute lymphoblastic leukemia (BCP-ALL) in children has shown eminent progress over the past decades, about 15% of patients can still not be cured, however. Therefore, new therapeutic strategies are warranted.

FOXO1 together with other transcription factors including EBF1, PAX5 and TCF3 plays a central role in differentiation of pre-B-cells. In cooperation with PAX5 and other B-cell transcription factors, FOXO1 induces expression of SYK, BLNK, RAG1, RAG2, AICDA and IL7RA genes. Of note, SYK and IL7RA signaling contribute to the oncogenic program of BCP-ALL, which utilize pre-B cell survival and proliferation program.

In this study, we demonstrate that FOXO1 is highly expressed in most of the BCP-ALL cell lines. By using immunofluorescence assays we show that FOXO1 is localized in the nucleus of BCP-ALL cells. Overexpression of constitutively active AKT1 (inactivating FOXO1) negatively regulates the growth of BCP-ALL cells. Inhibition of FOXO1 by shRNA results in cell death in the RS4;11 BCP-ALL cell line. BCP-ALL cells are more sensitive to growth arrest and apoptosis induced by a small molecular FOXO1 inhibitor AS1842856 than other classical Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Gene expression profiling of BCP-ALL cells after treatment with the FOXO1 inhibitor for 24h shows the significantly down-regulation of FOXO target genes including VPREB3, IL1B, KLHL24 and BNIP3L. Interestingly, at the same time, some FOXO targets like NOXA, RUNX2 and PRDM1 were found upregulated, indicating a complex effect of the FOXO1 inhibitor.

We conclude that FOXO1 expression is critical for the BCP-ALL oncogenic program and its targeting represents a novel therapeutic approach.

Citation Format: Fan Wang, Alexey Ushmorov, Thomas Wirth. Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2009.