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. 2020 Nov;24(22):12920-12932.
doi: 10.1111/jcmm.15882. Epub 2020 Oct 1.

Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells

Tamao Shinohara  1 , Kevin Y Urayama  2   3 , Atsushi Watanabe  1 , Koshi Akahane  1 , Kumiko Goi  1 , Meixian Huang  1 , Keiko Kagami  1 , Masako Abe  1 , Kanji Sugita  1 , Yukinori Okada  4 , Hiroaki Goto  5 , Masayoshi Minegishi  6 , Shotaro Iwamoto  7 , Takeshi Inukai  1
Affiliations

Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells

Tamao Shinohara et al. J Cell Mol Med. 2020 Nov.

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 × 10-8 ), 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 × 10-6 ), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10-8 ), 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.

Keywords: acute lymphoblastic leukaemia; genome-wide association studies; glucocorticoid sensitivity.

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Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Association between inherited genetic variants and sensitivity to prednisolone
Figure 2
Figure 2
Association between inherited genetic variants and sensitivity to dexamethasone
Figure 3
Figure 3
Association of FRMD4B, MITF, and TGFBR3 with glucocorticoid sensitivity
Figure 4
Figure 4
Association of inherited genetic variants with glucocorticoid receptor gene expression
Figure 5
Figure 5
Correlation between inherited genetic variants associated with prednisolone sensitivity and those with glucocorticoid receptor gene expression
See this image and copyright information in PMC

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