The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes
Peipei Lin,
Yanling Ren,
Xiaomei Yan,
Yingwan Luo,
Hua Zhang,
Meenu Kesarwani,
Jiachen Bu,
Di Zhan,
Yile Zhou,
Yuting Tang,
Shuanghong Zhu,
Weilai Xu,
Xinping Zhou,
Chen Mei,
Liya Ma,
Li Ye,
Chao Hu,
Mohammad Azam,
Wei Ding,
Jie Jin,
Gang Huang,
Hongyan Tong
Affiliations
Peipei Lin
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Yanling Ren
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Xiaomei Yan
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Yingwan Luo
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Hua Zhang
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Meenu Kesarwani
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Jiachen Bu
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Di Zhan
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Yile Zhou
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Yuting Tang
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Shuanghong Zhu
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Weilai Xu
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Xinping Zhou
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Chen Mei
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Liya Ma
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Li Ye
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Chao Hu
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China
Mohammad Azam
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Wei Ding
Department of Pathology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Jie Jin
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China
Gang Huang
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Hongyan Tong
Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, China;Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Although cytarabine has been widely considered as one of the chemotherapy drugs for high-risk myelodysplastic syndromes (MDS), the overall response rate is only approximately 20-30%. Nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. However, it is not yet known whether NRF2 can be used as a prognostic biomarker in MDS, or whether elevated NRF2 levels are associated with cytarabine resistance. Here, we found that NRF2 expression levels in bone marrow from high-risk patients exceeded that of low-risk MDS patients. Importantly, high NRF2 levels are correlated with inferior outcomes in MDS patients (n=137). Downregulation of NRF2 by the inhibitor Luteolin, or lentiviral shRNA knockdown, enhanced the chemotherapeutic efficacy of cytarabine, while MDS cells treated by NRF2 agonist Sulforaphane showed increased resistance to cytarabine. More importantly, pharmacological inhibition of NRF2 could sensitize primary high-risk MDS cells to cytarabine treatment. Mechanistically, downregulation of dual specificity protein phosphatase 1, an NRF2 direct target gene, could abrogate cytarabine resistance in NRF2 elevated MDS cells. Silencing NRF2 or dual specificity protein phosphatase 1 also significantly sensitized cytarabine treatment and inhibited tumors in MDS cells transplanted mouse models in vivo. Our study suggests that targeting NRF2 in combination with conventional chemotherapy could pave the way for future therapy for high-risk MDS.
