Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia
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 re...
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.634956/full |
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| author | Haiyan Liu Ziping Li Ziping Li Fei Qiu Chunjie Li Xiaojing Lin Yingyi He Maoxiang Qian Yuanbin Song Hui Zhang |
| author_facet | Haiyan Liu Ziping Li Ziping Li Fei Qiu Chunjie Li Xiaojing Lin Yingyi He Maoxiang Qian Yuanbin Song Hui Zhang |
| author_sort | Haiyan Liu |
| collection | DOAJ |
| description | 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 NR3C1 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 NR3C1 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 NR3C1 mutations (p. R477H, p. Y478C, p. P530fs, and p. H726P) were loss-of-function (LoF) mutations. A drug sensitivity test further showed that LoF NR3C1 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 NR3C1 may play a critical role in GC resistance and contribute to ALL treatment failure and/or relapse. |
| first_indexed | 2024-12-17T09:06:49Z |
| format | Article |
| id | doaj.art-998014c3b1524db7a03f6d1a30ae9796 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-17T09:06:49Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-998014c3b1524db7a03f6d1a30ae97962022-12-21T21:55:27ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-03-011210.3389/fphar.2021.634956634956Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic LeukemiaHaiyan Liu0Ziping Li1Ziping Li2Fei Qiu3Chunjie Li4Xiaojing Lin5Yingyi He6Maoxiang Qian7Yuanbin Song8Hui Zhang9Department of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaDepartment of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaInstitute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaBioinspired Engineering and Biomechanics Center, Xi’an Jiaotong University, Xi’an, ChinaDepartment of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaDepartment of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaDepartment of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaInstitute of Pediatrics and Department of Hematology and Oncology, Children's Hospital of Fudan University, National Children's Medical Center, the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaState Key Laboratory of Oncology in South China, Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, ChinaDepartment of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, ChinaTreatment 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 NR3C1 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 NR3C1 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 NR3C1 mutations (p. R477H, p. Y478C, p. P530fs, and p. H726P) were loss-of-function (LoF) mutations. A drug sensitivity test further showed that LoF NR3C1 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 NR3C1 may play a critical role in GC resistance and contribute to ALL treatment failure and/or relapse.https://www.frontiersin.org/articles/10.3389/fphar.2021.634956/fullglucocorticoidglucocorticoid receptordrug resistanceNR3C1acute lymphoblastic leukemia |
| spellingShingle | Haiyan Liu Ziping Li Ziping Li Fei Qiu Chunjie Li Xiaojing Lin Yingyi He Maoxiang Qian Yuanbin Song Hui Zhang Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia Frontiers in Pharmacology glucocorticoid glucocorticoid receptor drug resistance NR3C1 acute lymphoblastic leukemia |
| title | Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia |
| title_full | Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia |
| title_fullStr | Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia |
| title_full_unstemmed | Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia |
| title_short | Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia |
| title_sort | association between nr3c1 mutations and glucocorticoid resistance in children with acute lymphoblastic leukemia |
| topic | glucocorticoid glucocorticoid receptor drug resistance NR3C1 acute lymphoblastic leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.634956/full |
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