van der Zwet Jordy C G, Smits Willem, Buijs-Gladdines Jessica G C A M, Pieters Rob, Meijerink Jules P P
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Hemasphere. 2020 Dec 21;5(1):e513. doi: 10.1097/HS9.0000000000000513. eCollection 2021 Jan.
The glucocorticoid receptor NR3C1 is essential for steroid-induced apoptosis, and deletions of this gene have been recurrently identified at disease relapse for acute lymphoblastic leukemia (ALL) patients. Here, we demonstrate that recurrent NR3C1 inactivating aberrations-including deletions, missense, and nonsense mutations-are identified in 7% of pediatric T-cell ALL patients at diagnosis. These aberrations are frequently present in early thymic progenitor-ALL patients and relate to steroid resistance. Functional modeling of NR3C1 aberrations in pre-B ALL and T-cell ALL cell lines demonstrate that aberrations decreasing NR3C1 expression are important contributors to steroid resistance at disease diagnosis. Relative messenger RNA expression in primary diagnostic patient samples, however, does not correlate with steroid response.
糖皮质激素受体NR3C1对于类固醇诱导的细胞凋亡至关重要，并且在急性淋巴细胞白血病（ALL）患者疾病复发时，该基因的缺失已被反复发现。在此，我们证明在7%的儿童T细胞ALL患者诊断时可发现复发性NR3C1失活畸变，包括缺失、错义突变和无义突变。这些畸变在早期胸腺祖细胞ALL患者中经常出现，并且与类固醇耐药相关。在前B ALL和T细胞ALL细胞系中对NR3C1畸变进行功能建模表明，降低NR3C1表达的畸变是疾病诊断时类固醇耐药的重要因素。然而，原发性诊断患者样本中的相对信使RNA表达与类固醇反应无关。
