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Myelodysplastic Syndromes
The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):485-496
Peipei Lin,1,2,3,4* Yanling Ren,1,2,3* Xiaomei Yan,4 Yingwan Luo,1,2,3
Hua Zhang,1,2,3 Meenu Kesarwani,4 Jiachen Bu,4 Di Zhan,4 Yile Zhou,1,2,4 Yuting Tang,4 Shuanghong Zhu,1,2,3 Weilai Xu,1,2,3 Xinping Zhou,1,2,3
Chen Mei,1,2,3 Liya Ma,1,2,3 Li Ye,1,2,3 Chao Hu,1,2 Mohammad Azam,4 Wei Ding,5 Jie Jin,1,2 Gang Huang4# and Hongyan Tong1,2,3#
1Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Institute of Hematology, Zhejiang University, Hangzhou, China; 3Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 4Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA and 5Department of Pathology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
*PL and YR contributed equally to this work. #HYT and GH contributed equally to this study as joint senior authors.
ABSTRACT
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 elevat- ed 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 cytara- bine treatment. Mechanistically, downregulation of dual specificity pro- tein phosphatase 1, an NRF2 direct target gene, could abrogate cytara- bine 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 con- ventional chemotherapy could pave the way for future therapy for high- risk MDS.
Introduction
Myelodysplastic syndromes (MDS) are a heterogeneous disease of clonal hematopoietic stem cell neoplasms characterized by ineffective hematopoiesis, cytopenia, dysplasia of the myeloid cells, and an inherent risk of progression to acute myeloid leukemia (AML).1 There are several prognostic scores, and the International Prognostic Scoring System (IPSS) and its revised vision (IPSS-R) are commonly used to stratify patients into two risk groups, defining lower and higher risk patients.2,3 Higher risk MDS patients have an increased risk of developing AML and are associated with poor clinical outcomes. Treatment strategies were made
Correspondence:
HONGYAN TONG
tonghongyan@zju.edu.cn
GANG HUANG
Gang.Huang@cchmc.org
Received: May 15, 2018.
Accepted: September 26, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.197749
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