尽管 NOTCH1 表达，γ-分泌酶抑制剂也不会诱导成人 T 细胞白血病细胞系发生细胞毒性。
Gamma-secretase inhibitor does not induce cytotoxicity in adult T-cell leukemia cell lines despite NOTCH1 expression.
机构信息
Cancer Center, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Department of Clinical Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
出版信息
BMC Cancer. 2022 Oct 15;22(1):1065. doi: 10.1186/s12885-022-10003-w.
BACKGROUND
Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection.
METHODS
We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation.
RESULTS
Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines.
CONCLUSIONS
These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.
背景
NOTCH1 激活突变是 T 细胞型急性淋巴细胞白血病/淋巴瘤的驱动因素。γ-分泌酶抑制剂（GSI）可抑制 NOTCH1 的功能，有望成为一种靶向分子药物。NOTCH1 也在其他恶性肿瘤中表达。我们旨在确定 NOTCH1 表达的功能以及 GSI 对由长期人类 T 细胞白血病病毒 I 型（HTLV-1）感染引起的成人 T 细胞白血病/淋巴瘤（ATL）的影响。
方法
我们分析了六种 ATL 和 HTLV-1 感染的细胞系中 NOTCH1 的表达情况，并研究了激活的 NOTCH1（即 NOTCH1 的裂解形式）与 GSI 一起对细胞增殖的影响。
结果
无论 Tax 表达（HTLV-1 编码蛋白）如何，用 GSI 孵育后，在 ATL 和 HTLV-1 感染的细胞系中均检测不到激活的 NOTCH1。全外显子组测序显示，无论 NOTCH1 表达丰富与否，在六种 ATL 和 HTLV-1 感染的细胞系中均未检测到激活的 NOTCH1 突变。此外，GSI 并未抑制 ATL 细胞系的生长。
结论
这些发现表明，NOTCH1 蛋白持续激活，但在 NOTCH1 突变阴性 ATL 细胞增殖过程中可能是过客。
Zotero 插件