Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.
Department of Social Medicine, National Center for Child Health and Development, Tokyo, Japan.
J Cell Mol Med. 2020 Nov;24(22):12920-12932. doi: 10.1111/jcmm.15882. Epub 2020 Oct 1.
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 ), 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 ), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10 ), 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.
鉴定与白血病细胞糖皮质激素(GC)敏感性相关的遗传变异可能有助于深入了解潜在的药物靶点和靶向治疗。本研究在 72 株源自日本 B 细胞前体急性淋巴细胞白血病(ALL)患者的白血病细胞系中,进行了单核苷酸多态性(SNP)的全基因组基因分型,并试图鉴定与 GC 敏感性和 NR3C1(GC 受体)基因表达相关的遗传变异。使用 alamarBlue 细胞活力测定法可获得泼尼松龙(Pred)和地塞米松(Dex)的 IC50 测量值。Pred 的 IC50 值与位于 FRMD4B 和 MITF 基因之间的 rs904419 (P=4.34×10)最强相关。rs904419 AA(n=13)、AG(n=31)和 GG(n=28)基因型的白血病细胞系的中位 Pred IC50 值分别为 0.089、0.139 和 297µmol/L。对于地塞米松敏感性,TGFBR3 基因的同义 SNP rs2306888 (P=1.43×10)观察到提示性关联。对于 NR3C1 基因表达,PLEKHA8 基因中的 SNP rs11982167 (P=6.44×10)观察到提示性关联。这些遗传变异可能影响 ALL 细胞的 GC 敏感性,并为 ALL 患者有效和安全化疗的个性化医学提供机会。