细胞毒性T细胞
癌症研究
生物
DNMT1型
谱系(遗传)
基因敲除
甲基转移酶
基因
遗传学
甲基化
体外
作者
Sudipta Biswas,Kai Kang,Kwok Peng Ng,Tomas Radivoyevitch,Kurt A. Schalper,Zhang Hua,Daniel J. Lindner,Anish Thomas,David MacPherson,Brian Gastman,David S. Schrump,Kwok‐Kin Wong,Vamsidhar Velcheti,Yogen Saunthararajah
出处
期刊:Cell Reports
[Elsevier]
日期:2023-08-01
卷期号:42 (8): 113016-113016
被引量:2
标识
DOI:10.1016/j.celrep.2023.113016
摘要
Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.
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