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Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.
- Source :
-
Cancer medicine [Cancer Med] 2019 Sep; Vol. 8 (11), pp. 5274-5288. Date of Electronic Publication: 2019 Jul 15. - Publication Year :
- 2019
-
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.<br /> (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2045-7634
- Volume :
- 8
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31305009
- Full Text :
- https://doi.org/10.1002/cam4.2356