Oncotarget

Research Papers:

HPRT1 activity loss is associated with resistance to thiopurine in ALL

Fan Yang, Houshun Fang, Dan Wang, Yao Chen, Yonggong Zhai, Bin-Bing S. Zhou and Hui Li _

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Oncotarget. 2018; 9:2268-2278. https://doi.org/10.18632/oncotarget.23405

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Abstract

Fan Yang1,2,3,*, Houshun Fang2,3,*, Dan Wang2,3,*, Yao Chen2,3, Yonggong Zhai1, Bin-Bing S. Zhou2,3,4 and Hui Li2,3,4

1Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China

2Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4Department of Pharmacology and Chemical Biology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China

*These authors contributed equally to this work

Correspondence to:

Hui Li, email: [email protected]

Bin-Bing S. Zhou, email: [email protected]

Keywords: thiopurine; leukemia; drug resistance; HPRT1 mutation; purine metabolism

Received: August 02, 2017    Accepted: December 03, 2017    Published: December 19, 2017

ABSTRACT

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Thiopurine is a widely used drug in the maintaining treatment of ALL. After a period of chemotherapy, 20% of pediatric patients and over 50% of adult patients will relapse. To investigate the mechanisms of drug resistance in vitro, we established the thiopurine resistant cell lines Reh-6MPR (6-MP Resistant cell) and Reh-6TGR (6-TG Resistant cell) by stepwise selection of the ALL cell line Reh. Cell viability assay revealed that 6MPR and 6TGR cells were almost 1000-fold more resistant to thiopurine comparing with the control Reh cells, and thiopurine conversion was significantly impaired in the resistant cells. Mechanistically, a same novel hypoxanthine phosphoribosyl transferase 1 (HPRT1) mutation c.495_496insA (p.V165fs) was found by whole exome sequencing in both resistant cells. The HPRT1 mutation dramaticly decreased the production of [13C5,15N4]-IMP from [13C5,15N4]-hypoxanthine (HX), showed a loss-of-funciton mechanism. Notably, re-expression the wildtype HPRT1 in Reh-6MPR cell can reverse the drug resistance and thiopurine conversion in Reh-6MPR cells. These results highlight the importance of HPRT1’s activity in thiopurine resistance.


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