Impact of MicroRNA Polymorphisms on High-dose Methotrexate-related Hematological Toxicities in Pediatric Acute Lymphoblastic Leukemia

Overview

Journal Front Pediatr

Specialty Pediatrics

Date 2023 Jun 29

PMID 37384310

Authors

Min Zhan

Ting Liu

Zhou Zhang

Guoqiang Wang

Zhongqiang Cao

Xuejuan Li

Hongwu Zeng

Huirong Mai

Zebin Chen

Affiliations

Soon will be listed here.

Abstract

Objectives: It is well known that transporter and enzyme genes could be regulated by microRNA (miRNA) at the post-transcriptional level, and single-nucleotide polymorphisms (SNPs) in miRNA, which are involved in the miRNA production and structure, may impact the miRNA expression level and then influence drug transport and metabolism. In this study, we aim to evaluate the association between miRNA polymorphisms and high-dose methotrexate (HD-MTX) hematological toxicities in Chinese pediatric patients with acute lymphoblastic leukemia (ALL).

Method: A total of 181 children with ALL were administered with 654 evaluable cycles of HD-MTX. Their hematological toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5. The association between 15 candidate SNPs of miRNA and hematological toxicities (leukopenia, anemia, and thrombocytopenia) was analyzed using Fisher's exact test. Further multiple backward logistic regression analysis was used to explore the independent risk factors for grade 3/4 hematological toxicities.

Result: Rs2114358 G>A in pre-hsa-miR-1206 was related to HD-MTX-related grade 3/4 leukopenia after multiple logistic regression [GA + AA vs. GG: odds ratio (OR): 2.308, 95% CI: 1.219-4.372, = 0.010], and rs56103835 T > C in pre-hsa-mir-323b was associated with HD-MTX-related grade 3/4 anemia (TT + TC vs. CC: OR: 0.360, 95% CI: 0.239-0.541, = 0.000); none of the SNPs were significantly associated with grade 3/4 thrombocytopenia. Bioinformatics tools predicted that rs2114358 G>A and rs56103835 T>C would impact the secondary structure of pre-miR-1206 and pre-miR-323b, respectively, and then probably influence the expression level of mature miRNAs and their target genes.

Conclusion: Rs2114358 G>A and rs56103835 T>C polymorphism may potentially influence HD-MTX-related hematological toxicities, which may serve as candidate clinical biomarkers to predict grade 3/4 hematological toxicities in pediatric patients with ALL.

Citing Articles

Association of Gene Polymorphisms and Its Regulatory miRNAs with Methotrexate Toxicity in Children with Acute Lymphoblastic Leukemia.

Karpa V, Kalinderi K, Gavriilaki E, Antari V, Hatzipantelis E, Katopodi T Curr Issues Mol Biol. 2024; 46(10):11537-11547.

PMID: 39451565 PMC: 11505744. DOI: 10.3390/cimb46100685.

Advancements in the Regulatory Role of microRNAs in Childhood Acute Lymphoblastic Leukemia: Mechanisms and Clinical Implications.

Deng W Technol Cancer Res Treat. 2024; 23:15330338241273143.

PMID: 39099455 PMC: 11301750. DOI: 10.1177/15330338241273143.

Association of microRNA Polymorphisms with Toxicities Induced by Methotrexate in Children with Acute Lymphoblastic Leukemia.

Karpa V, Kalinderi K, Fidani L, Tragiannidis A Hematol Rep. 2023; 15(4):634-650.

PMID: 37987321 PMC: 10660515. DOI: 10.3390/hematolrep15040065.

References

Wang S, Zeng W, Wu W, Sun L, Yan D . Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia. J Gene Med. 2017; 19(11):353-359. DOI: 10.1002/jgm.2990. View

Graves P, Zeng Y . Biogenesis of mammalian microRNAs: a global view. Genomics Proteomics Bioinformatics. 2012; 10(5):239-45. PMC: 5054211. DOI: 10.1016/j.gpb.2012.06.004. View

Li M, Chang H, Yang Y, Lu M, Shao P, Fu C . Infectious complications in children with acute lymphoblastic leukemia treated with the Taiwan Pediatric Oncology Group protocol: A 16-year tertiary single-institution experience. Pediatr Blood Cancer. 2017; 64(10). DOI: 10.1002/pbc.26535. View

DiPaolo A, Chu E . The role of thymidylate synthase as a molecular biomarker. Clin Cancer Res. 2004; 10(2):411-2. DOI: 10.1158/1078-0432.ccr-1198-03. View

Lopez-Lopez E, Gutierrez-Camino A, Pinan M, Sanchez-Toledo J, Uriz J, Ballesteros J . Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric acute lymphoblastic leukemia. PLoS One. 2014; 9(3):e91261. PMC: 3948785. DOI: 10.1371/journal.pone.0091261. View

Yu S, Kim J, Lee J, Yoon J, Lee H, Cheong J . Association of a microRNA-323b polymorphism with the persistence of hepatitis B virus infection by the enhancement of viral replication. J Viral Hepat. 2013; 21(12):853-9. DOI: 10.1111/jvh.12215. View

Gutierrez-Camino A, Umerez M, Lopez-Lopez E, Santos-Zorrozua B, Martin-Guerrero I, Garcia de Andoin N . Involvement of miRNA polymorphism in mucositis development in childhood acute lymphoblastic leukemia treatment. Pharmacogenomics. 2018; 19(18):1403-1412. DOI: 10.2217/pgs-2018-0113. View

Wang S, Sun L, Zeng W, Wu W, Zhang G . Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2014; 74(2):283-9. DOI: 10.1007/s00280-014-2507-8. View

Chaabane S, Messedi M, Akrout R, Ben Hamad M, Turki M, Marzouk S . Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients. Inflamm Res. 2018; 67(8):703-710. DOI: 10.1007/s00011-018-1161-8. View

10.

Gutierrez-Camino A, Martin-Guerrero I, Dolzan V, Jazbec J, Carbone-Baneres A, Garcia de Andoin N . Involvement of SNPs in miR-3117 and miR-3689d2 in childhood acute lymphoblastic leukemia risk. Oncotarget. 2018; 9(33):22907-22914. PMC: 5955428. DOI: 10.18632/oncotarget.25144. View

11.

Hu Y, Zhou L, Wang S, Jing X, Guo H, Sun F . Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters. Curr Pharm Des. 2019; 25(6):627-634. DOI: 10.2174/1381612825666190329141003. View

12.

Iparraguirre L, Gutierrez-Camino A, Umerez M, Martin-Guerrero I, Astigarraga I, Navajas A . MiR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia. Pharmacogenet Genomics. 2016; 26(11):517-525. DOI: 10.1097/FPC.0000000000000245. View

13.

Lampropoulou D, Aravantinos G, Laschos K, Theodosopoulos T, Papadimitriou C, Gazouli M . MiR-218 and miR-100 polymorphisms as markers of irinotecan-based chemotherapy response in metastatic colorectal cancer. Int J Colorectal Dis. 2019; 34(11):1871-1877. DOI: 10.1007/s00384-019-03401-3. View

14.

Martin-Guerrero I, Gutierrez-Camino A, Lopez-Lopez E, Bilbao-Aldaiturriaga N, Pombar-Gomez M, Ardanaz M . Genetic variants in miRNA processing genes and pre-miRNAs are associated with the risk of chronic lymphocytic leukemia. PLoS One. 2015; 10(3):e0118905. PMC: 4368096. DOI: 10.1371/journal.pone.0118905. View

15.

Wang S, Zeng W, Wu W, Sun L, Yan D . Association between a microRNA binding site polymorphism in SLCO1A2 and the risk of delayed methotrexate elimination in Chinese children with acute lymphoblastic leukemia. Leuk Res. 2018; 65:61-66. DOI: 10.1016/j.leukres.2018.01.004. View

16.

Kim H, Prokunina-Olsson L, Chanock S . Common genetic variants in miR-1206 (8q24.2) and miR-612 (11q13.3) affect biogenesis of mature miRNA forms. PLoS One. 2012; 7(10):e47454. PMC: 3471815. DOI: 10.1371/journal.pone.0047454. View

17.

de Jonge R, Hooijberg J, van Zelst B, Jansen G, Jansen G, van Zantwijk C . Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood. 2005; 106(2):717-20. DOI: 10.1182/blood-2004-12-4941. View

18.

Oosterom N, Berrevoets M, den Hoed M, Zolk O, Hoerning S, Pluijm S . The role of genetic polymorphisms in the thymidylate synthase (TYMS) gene in methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Pharmacogenet Genomics. 2018; 28(10):223-229. DOI: 10.1097/FPC.0000000000000352. View

19.

Fernandez N, Cordiner R, Young R, Hug N, Macias S, Caceres J . Genetic variation and RNA structure regulate microRNA biogenesis. Nat Commun. 2017; 8:15114. PMC: 5418625. DOI: 10.1038/ncomms15114. View

20.

Gutierrez-Camino A, Oosterom N, den Hoed M, Lopez-Lopez E, Martin-Guerrero I, Pluijm S . The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet Genomics. 2017; 27(8):303-306. DOI: 10.1097/FPC.0000000000000291. View