MAP4K1 Functions as a Tumor Promotor and Drug Mediator for AML <i>via</i> Modulation of DNA Damage/Repair System and MAPK Pathway

Abstract

Background: Acute myeloid leukemia (AML) is a group of heterogeneous hematologic malignancies with poor prognosis. Finding core biomarkers was an ugent need. Kinases are involved in many regulatory pathways and biological activities in AML. MAP4K1 encodes a serine / threonine protein kinase that is involved in various signaling pathways, however, its role and mechanism in acute myeloid leukemia (AML) has not been explored. Methods: RNA-seq profiling was performed for HHT-resistant and HHT-sensitive cell lines. Bioinformatics were used to make differential analysis. Cell culture and transfection, cell proliferation, apoptosis and cell cycle assay, Quantitative RT-PCR and Western blotting analysis were used to explore biological phenotypes in vitro. Findings: In this study, high expression levels of MAP4K1 were observed in Homoharringtonine (HHT) -induced resistant AML cell lines. In addition, overexpression of MAP4K1 in AML cells induces resistance of AML cells to HHT. Not only that, the findings of this study show that overexpression of MAP4K1 is an independent risk factor for poor prognosis of AML. Further, the results show that expression of MAP4K1 modulates cell cycle through MAPK and DNA damage pathways. Therefore, MAP4K1 is a potential target for development of AML therapy. Interpretation: This study demonstrates that MAP4K1 was not only a mediator of HHT resistance but an independent risk factor for AML prognosis. In addition, information on regulatory mechanism of MAP4K1 provides a novel treatment strategy for resistant and refractory AML. Fundings: This work was supported by National Natural Science Foundation of China (NSFC) (Grant No.81800199, 81670124, 82070118) and the Natural Science Foundation of Zhejiang Province (LY20H080008). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee.