Liu Haiyan, Li Ziping, Qiu Fei, Li Chunjie, Lin Xiaojing, He Yingyi, Qian Maoxiang, Song Yuanbin, Zhang Hui
Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Front Pharmacol. 2021 Mar 29;12:634956. doi: 10.3389/fphar.2021.634956. eCollection 2021.
Treatment outcomes in children with acute lymphoblastic leukemia (ALL) have been improved substantially, with a cure rate exceeding 80% using conventional therapy. However, the outcome for patients with relapsed/refractory ALL remains unsatisfactory, despite the fact that these patients generally receive more intense therapy. Glucocorticoid (GC) resistance is a leading cause of treatment failure and relapse in ALL. Abnormal transcription and/or translation is strongly associated with GC resistance, but the underlying molecular mechanism and the clinical value of NR3C1 alterations with GC resistance in ALL treatment remain unclear. This study applied panel sequencing to 333 newly diagnosed and 18 relapsed ALL samples to characterize the link between NR3C1 and ALL further. We identified mutations in three patients with newly diagnosed ALL (0.9%) and two patients with relapsed ALL (11.1%). Functional analyses revealed that four of these five mutations (p. R477H, p. Y478C, p. P530fs, and p. H726P) were loss-of-function (LoF) mutations. A drug sensitivity test further showed that LoF mutations influence GC resistance. Saturated mutagenesis of hotspot R477 demonstrated the importance of this residue for NR3C1 function. The dominant-negative effect of p. R477C and p. R477S and the non-dominant negative effect of p. R477H and p. Y478C suggests multiple mechanisms underlying GC resistance. Thus, primary or acquired genomic lesions in may play a critical role in GC resistance and contribute to ALL treatment failure and/or relapse.
急性淋巴细胞白血病（ALL）患儿的治疗效果已得到显著改善，采用传统疗法的治愈率超过80%。然而，复发/难治性ALL患者的治疗结果仍不尽人意，尽管这些患者通常接受更强化的治疗。糖皮质激素（GC）耐药是ALL治疗失败和复发的主要原因。异常转录和/或翻译与GC耐药密切相关，但NR3C1改变在ALL治疗中与GC耐药相关的潜在分子机制及临床价值仍不清楚。本研究对333例新诊断和18例复发的ALL样本进行了panel测序，以进一步明确NR3C1与ALL之间的联系。我们在3例新诊断ALL患者（0.9%）和2例复发ALL患者（11.1%）中发现了突变。功能分析显示，这5个突变中的4个（p.R477H、p.Y478C、p.P530fs和p.H726P）为功能丧失（LoF）突变。药物敏感性试验进一步表明，LoF突变影响GC耐药。热点R477的饱和诱变证明了该残基对NR3C1功能的重要性。p.R477C和p.R477S的显性负效应以及p.R477H和p.Y478C的非显性负效应提示GC耐药存在多种机制。因此，NR3C1的原发性或获得性基因组损伤可能在GC耐药中起关键作用，并导致ALL治疗失败和/或复发。
