MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway
Qing Ling,
Fenglin Li,
Xiang Zhang,
Shihui Mao,
Xiangjie Lin,
Jiajia Pan,
Wenle Ye,
Wenwen Wei,
Yu Qian,
Chao Hu,
Xin Huang,
Jinghan Wang,
Huafeng Wang,
Jiansong Huang,
Yungui Wang,
Jie Jin
Affiliations
Qing Ling
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Fenglin Li
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Xiang Zhang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Shihui Mao
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Xiangjie Lin
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Jiajia Pan
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Wenle Ye
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Wenwen Wei
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Yu Qian
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Chao Hu
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Xin Huang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Jinghan Wang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Huafeng Wang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Jiansong Huang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Yungui Wang
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China
Jie Jin
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang, China; Corresponding author at: Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, China.
Background: Acute myeloid leukemia (AML) is a group of heterogeneous hematologic malignancies correlates with poor prognosis. It is important to identify biomarkers for effective treatment of AML. Kinases participate in many regulatory pathways and biological activities in AML. Previous studies demonstrated that MAP4K1, a serine/threonine kinase, was associated with immune regulation and cancer progression. However, its role and mechanism in acute myeloid leukemia (AML) have not been explored.Methods: RNA-seq profiling was performed for Homoharringtonine (HHT)-resistant and Homoharringtonine (HHT)-sensitive cell lines. Bioinformatic tools were used for 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: We found that MAP4K1 was highly expressed in HHT-induced resistant AML cell lines. In addition, overexpression of MAP4K1 in AML cells induced resistance of AML cells against HHT. Not only that, the findings of this study showed that overexpression of MAP4K1 was an independent risk factor that predicts poor prognosis of AML. Further, In vitro studies showed that MAP4K1 modulated cell cycle through MAPK and DNA damage/repair pathways. Therefore, MAP4K1 is a potential target for developing therapies for AML.Interpretation: This study demonstrates that MAP4K1 not only regulates HHT resistance but also independently predicts AML prognosis. In addition, understanding the regulatory mechanism of MAP4K1 reveals novel treatment strategies for resistant and refractory AML.Fundings: This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No.81800199, 81670124, 82070118) and the Natural Science Foundation of Zhejiang Province (LY20H080008).
