Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymp
- PDF / 835,387 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 42 Downloads / 159 Views
PRIMARY RESEARCH
Cancer Cell International Open Access
Association of relapse‑linked ARID5B single nucleotide polymorphisms with drug resistance in B‑cell precursor acute lymphoblastic leukemia cell lines Minori Tamai1, Meixian Huang1, Keiko Kagami1, Masako Abe1, Shinpei Somazu1, Tamao Shinohara1, Daisuke Harama1, Atsushi Watanabe1, Koshi Akahane1, Kumiko Goi1, Kanji Sugita1,2, Hiroaki Goto3, Masayoshi Minegishi4, Shotaro Iwamoto5 and Takeshi Inukai1*
Abstract Background: The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents. Methods: We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment. Results: No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p = 0.031 in Mann–Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p = 0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml). Conclusion: These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.
*Correspondence: [email protected] 1 Department of Pediatrics, School of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 1110, Japan Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International
Data Loading...
