Abstract

Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

Highlights

  • Acute myeloid leukemia (AML) is a highly heterogeneous clonal hematologic disease characterized by genetic and epigenetic alterations leading to the proliferation and expansion of abnormal myeloid stem/precursor cells in blood and bone marrow [1]

  • These results suggest that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP are associated with poor prognosis in AML patients

  • In the presence of doxycycline, we observed a robust induction of p53 upregulated modulator of apoptosis (PUMA) at both the mRNA and protein levels in KG1a and MOLM-13 cells transfected with WTIP vector (Fig. 3D, E), suggesting that PUMA is involved in WTIP overexpression induced apoptosis in AML cells

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Summary

INTRODUCTION

Acute myeloid leukemia (AML) is a highly heterogeneous clonal hematologic disease characterized by genetic and epigenetic alterations leading to the proliferation and expansion of abnormal myeloid stem/precursor cells in blood and bone marrow [1]. Forkhead box O (FOXO) proteins, including FOXO1, FOXO3a, FOXO4, and FOXO6, are a group of transcriptional factors that can modulate the expression of genes involved in apoptosis, cell cycle arrest, DNA repair, oxidative stress, and other cellular functions [7,8,9]. Higher levels of phosphorylated FOXO3a are an adverse prognostic factor in AML patients [13] These results suggest that FOXO3a is a tumor suppressor in AML. Upon transcriptional activation of FOXO3a, its downstream target p53 upregulated modulator of apoptosis (PUMA) is increased, leading to activation of the intrinsic apoptotic pathway. These results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

MATERIALS AND METHODS
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DISCUSSION

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