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Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2020 Nov; Vol. 24 (22), pp. 12920-12932. Date of Electronic Publication: 2020 Oct 01. - Publication Year :
- 2020
-
Abstract
- Identification of genetic variants associated with glucocorticoids (GC) sensitivity of leukaemia cells may provide insight into potential drug targets and tailored therapy. In the present study, within 72 leukaemic cell lines derived from Japanese patients with B-cell precursor acute lymphoblastic leukaemia (ALL), we conducted genome-wide genotyping of single nucleotide polymorphisms (SNP) and attempted to identify genetic variants associated with GC sensitivity and NR3C1 (GC receptor) gene expression. IC50 measures for prednisolone (Pred) and dexamethasone (Dex) were available using an alamarBlue cell viability assay. IC50 values of Pred showed the strongest association with rs904419 (P = 4.34 × 10 <superscript>-8</superscript> ), located between the FRMD4B and MITF genes. The median IC50 values of prednisolone for cell lines with rs904419 AA (n = 13), AG (n = 31) and GG (n = 28) genotypes were 0.089, 0.139 and 297 µmol/L, respectively. For dexamethasone sensitivity, suggestive association was observed for SNP rs2306888 (P = 1.43 × 10 <superscript>-6</superscript> ), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10 <superscript>-8</superscript> ), located in the PLEKHA8 gene. These genetic variants may affect GC sensitivity of ALL cells and may give rise to opportunities in personalized medicine for effective and safe chemotherapy in ALL patients.<br /> (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Subjects :
- Cell Line, Tumor
Dexamethasone pharmacology
Drug Screening Assays, Antitumor
Gene Expression Profiling
Genotype
Humans
Inhibitory Concentration 50
Japan
Pharmacogenetics
Polymorphism, Single Nucleotide
Prednisolone pharmacology
Receptors, Glucocorticoid genetics
Gene Expression Regulation, Leukemic
Genetic Variation
Glucocorticoids pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 24
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33002292
- Full Text :
- https://doi.org/10.1111/jcmm.15882