1. Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.
- Author
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Watanabe A, Inukai T, Kagami K, Abe M, Takagi M, Fukushima T, Fukushima H, Nanmoku T, Terui K, Ito T, Toki T, Ito E, Fujimura J, Goto H, Endo M, Look T, Kamps M, Minegishi M, Takita J, Inaba T, Takahashi H, Ohara A, Harama D, Shinohara T, Somazu S, Oshiro H, Akahane K, Goi K, and Sugita K
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Alleles, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Frequency, Genotype, Humans, Immunophenotyping, Mice, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 19, Drug Resistance, Neoplasm genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic
- Abstract
t(17;19)(q21-q22;p13), responsible for TCF3-HLF fusion, is a rare translocation in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL). t(1;19)(q23;p13), producing TCF3-PBX1 fusion, is a common translocation in childhood BCP-ALL. Prognosis of t(17;19)-ALL is extremely poor, while that of t(1;19)-ALL has recently improved dramatically in intensified chemotherapy. In this study, TCF3-HLF mRNA was detectable at a high level during induction therapy in a newly diagnosed t(17;19)-ALL case, while TCF3-PBX1 mRNA was undetectable at the end of induction therapy in most newly diagnosed t(1;19)-ALL cases. Using 4 t(17;19)-ALL and 16 t(1;19)-ALL cell lines, drug response profiling was analyzed. t(17;19)-ALL cell lines were found to be significantly more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)-ALL cell lines. Sensitivities to three (Pred, VCR, and l-asparaginase [l-Asp]), four (Pred, VCR, l-Asp, and DNR) and five (Pred, VCR, l-Asp, DNR, and cyclophosphamide) agents, widely used in induction therapy, were significantly poorer for t(17;19)-ALL cell lines than for t(1;19)-ALL cell lines. Consistent with poor responses to VCR and DNR, gene and protein expression levels of P-glycoprotein (P-gp) were higher in t(17;19)-ALL cell lines than in t(1;19)-ALL cell lines. Inhibitors for P-gp sensitized P-gp-positive t(17;19)-ALL cell lines to VCR and DNR. Knockout of P-gp by CRISPRCas9 overcame resistance to VCR and DNR in the P-gp-positive t(17;19)-ALL cell line. A combination of cyclosporine A with DNR prolonged survival of NSG mice inoculated with P-gp-positive t(17;19)-ALL cell line. These findings indicate involvement of P-gp in resistance to VCR and DNR in Pgp positive t(17;19)-ALL cell lines. In all four t(17;19)-ALL cell lines, RAS pathway mutation was detected. Furthermore, among 16 t(1;19)-ALL cell lines, multiagent resistance was usually observed in the cell lines with RAS pathway mutation in comparison to those without it, suggesting at least a partial involvement of RAS pathway mutation in multiagent resistance of t(17;19)-ALL., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2019
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