Molecular mechanism of c-Myc and PRPS1/2 against thiopurine resistance in Burkitt's lymphoma.

Ting Li,Yali Han,Yanxin Li,Liang Zheng,Shanshan Li,Yijin Gao,Zhiyan Zhan,Yingwen Zhang,Yuejia Tang,Siqi Wang,Yang Li,Yi Yang,Zhou Xv,Lili Song

doi:10.1111/jcmm.15322

Abstract

Patients with relapsed/refractory Burkitt's lymphoma (BL) have a dismal prognosis. Current research efforts aim to increase cure rates by identifying high‐risk patients in need of more intensive or novel therapy. The 8q24 chromosomal translocation of the c‐Myc gene, a main molecular marker of BL, is related to the metabolism by regulating phosphoribosyl pyrophosphate synthetase 2 (PRPS2). In our study, BL showed significant resistance to thiopurines. PRPS2 homologous isoenzyme, PRPS1, was demonstrated to play the main role in thiopurine resistance. c‐Myc did not have direct effects on thiopurine resistance in BL for only driving PRPS2. PRPS1 wild type (WT) showed different resistance to 6‐mercaptopurine (6‐mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback. PRPS1 A190T mutant could dramatically increase thiopurine resistance in BL. The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non‐Hodgkin's lymphoma in China (CCCG‐B‐NHL‐2015 study) confirms the value of high‐dose methotrexate (MTX) and cytarabine (ARA‐C) in high‐risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.

Highlights

Current research efforts aim to increase cure rates by identifying high-risk patients in need of more intensive or novel therapy. c-Myc gene which is typically overexpressed in Burkitt's lymphoma (BL) can regulate the metabolic changes of tumour cells by driving pyrophosphate synthetase 2 (PRPS2)
Our present study is to gain a better understanding of the roles of c-Myc and PRPS1/2 in thiopurine drug resistance in BL to identify a more suitable molecular target and potentially improve the treatment of BL
The Mannava's laboratory found that knocking out the c-Myc gene in human melanoma cell lines could reduce the expression of several rate-limiting enzymes during nucleotide synthesis, such as thymidylate synthase, HX nucleotide dehydrogenase 2 (IMPDH2) and PRPS2 resulting in a decrease in intracellular nucleotide levels and cell proliferation.[17]

Summary

| INTRODUCTION

We compared the characteristic of chemotherapy drug resistance in BL with that in leukaemia and dissected the roles of c-Myc, PRPS1 and PRPS2 in thiopurine drug resistance in BL. PRPS1 played the key role in thiopurine resistance which showed different resistance to the thiopurines in different metabolic cells for the feedback inhibition of ADP/GDP. The combination of thiopurine and the GART inhibitor lometrexol can increase the cell sensitivity to thiopurine resistance in BL. These results provide a new therapeutic strategy to overcome thiopurine drug resistance in BL

| MATERIALS AND METHODS

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| DISCUSSION