FBXW4 Is Highly Expressed and Associated With Poor Survival in Acute Myeloid Leukemia.

Qi Han,Yevgeniya Bamme,Zheng Ge,Huihui Song,Qi Zhang,Chunhua Song

doi:10.3389/fonc.2020.00149

Abstract

The F-box and WD repeat domain-containing (FBXW) proteins play an important role in ubiquitin proteasome by inducing protein degradation. Ten FBXW proteins have been identified in humans. The functions of FBXW proteins, like FBXW7, have been well-established in many human cancers. However, little is known about their transcriptional expression profiles and relationship with prognosis in acute myeloid leukemia (AML). Here we investigated the roles of FBXW proteins in AML by analyzing their mRNA expression profiles and association with clinical features using data from EMBL-EBI, the Cancer Cell Line Encyclopedia, Gene Expression Profiling Interactive Analysis, and cBioPortal databases. Our results showed that the mRNA level of FBXW proteins were highly detected by microarray in 14 AML cell lines, although there were no obvious differences. The expression of FBXW4 was significantly higher in AML patients compared with that in normal controls (P < 0.01). Patients whose age was ≥60 years old had a higher FBXW4 expression when compared with those who were <60 years old (P < 0.05). Cytogenetic favorable-risk group patients had a much lower FBXW4 expression than the intermediate- and poor-risk group patients (P < 0.0001). Moreover, patients with high FBXW4 expression exhibited significantly shorter event-free survival (EFS) and overall survival (OS) than those with low FBXW4 expression (median EFS: 5.3 vs. 10.0 months, P = 0.025; median OS: 8.1 vs. 19.0 months, P= 0.015). A multivariate analysis indicated that high FBXW4 expression was an independent risk factor for poor EFS in AML patients who received intensive chemotherapy followed by allo-SCT. In summary, our data suggested that FBXW4 is aberrantly expressed in AML and high FBXW4 expression might be a poor prognostic biomarker; future functional and mechanistic studies will further illuminate the roles of FBXW4 in AML.

Highlights

Acute myeloid leukemia (AML) is a hematopoietic malignancy originating from myeloid precursors and is the most common acute leukemia in adults [1]
Results indicated that FBXW5, FBXW11, FBXW2, FBXW9, FBXW4, FBXW8, and FBXW7 are well expressed in the cell lines, FBXW5 had the highest expression in the cells
Consistent with its expression characteristics in acute myeloid leukemia (AML) cell lines, FBXW5 mRNA level was higher in AML patients compared with other F-box and WD repeat domain-containing (FBXW) proteins (Figure 2B); it is higher in normal controls

Summary

Introduction

Acute myeloid leukemia (AML) is a hematopoietic malignancy originating from myeloid precursors and is the most common acute leukemia in adults [1]. AML is still incurable in 60–65% of patients who are 60 or younger due to refractory or relapsed disease. The substrates can bind to FBXW7 after they have been phosphorylated at specific sites [9] Most of these substrates have been identified as key molecules or transcription factors that play important roles in the regulation of cell growth and cell proliferation, such as cyclin E, MYC, and NOTCH [9,10,11,12,13,14]. In T-cell acute lymphoblastic leukemia and some solid tumors, many loss-of-function mutations have been identified in FBXW7 These mutations influence the interaction of FBXW7 with its substrates and impair their degradation [15, 16]. FBXW2 has been shown to be a tumor suppressor in lung cancer cells by promoting SKP2 degradation [17]

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Results

Conclusion