BIRC5 上调可提高 DNMT3A 突变 T-ALL 细胞的存活率和发病率

{"title":"BIRC5 上调可提高 DNMT3A 突变 T-ALL 细胞的存活率和发病率","authors":"","doi":"10.1016/j.bneo.2024.100040","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. <em>DNMT3A</em> mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with <em>DNMT3A</em> mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant <em>DNMT3A</em>, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene <em>BIRC5</em> was upregulated in patients with <em>DNMT3A</em>-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of <em>BIRC5</em> in vivo lead to rapid depletion of <em>DNMT3A</em>-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis\",\"authors\":\"\",\"doi\":\"10.1016/j.bneo.2024.100040\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Abstract</h3><div>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. <em>DNMT3A</em> mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with <em>DNMT3A</em> mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant <em>DNMT3A</em>, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene <em>BIRC5</em> was upregulated in patients with <em>DNMT3A</em>-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of <em>BIRC5</em> in vivo lead to rapid depletion of <em>DNMT3A</em>-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.</div></div>\",\"PeriodicalId\":100189,\"journal\":{\"name\":\"Blood Neoplasia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood Neoplasia\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2950328024000402\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328024000402","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

摘要T细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性造血肿瘤。虽然小儿 T-ALL 的预后随着化疗方案的加强而有所改善,但这种益处在很大程度上并没有转化到成人 T-ALL 群体中。开发新的治疗方法需要了解特定突变的驱动机制。在10%到18%的成人T-ALL患者中发现了DNMT3A突变,而且与不良的临床预后有关。在这里,我们利用原代人类标本表明,来自T-ALL患者的细胞如果存在DNMT3A突变,就会对细胞凋亡和某些化疗产生耐药性。JAK/STAT信号的升高推动了DNMT3A突变患者的促生存程序,抑制JAK/STAT可恢复对化疗的敏感性。在DNMT3A突变的T-ALL患者中,前生存基因BIRC5上调,这些细胞对含有IAP重复序列5的杆状病毒(Baculoviral IAP Repeat Containing 5,BIRC5)抑制剂YM155特别敏感。在体内对BIRC5进行基因抑制可迅速清除患者异种移植中的DNMT3A突变T-ALL细胞,从而将BIRC5定位为这些患者的精准医疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Lenalidomide, ixazomib, or daratumumab maintenance therapy in multiple myeloma BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice Augmented use of L-asparaginase markedly improves AYA ALL outcomes: FBMTG prospective MRD2014 study T-cell lymphoblastic lymphoma compared with T-cell acute lymphoblastic leukemia: similar subtypes and different fusions
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1