Our previous studies demonstrated that CCR9 plays an important role in several aspects of T-cell acute lymphoblastic leukemia progression and that CCR9 is a potential therapeutic target. However, the underlying mechanism that regulates CCR9 expression remains incompletely understood. In this study, bioinformatics analysis and validation in clinical samples revealed the lncRNA15691 to be positively correlated with CCR9 mRNA expression and significantly upregulated in T-cell acute lymphoblastic leukemia samples and CCR9high T-cell acute lymphoblastic leukemia cell lines. LncRNA15691, a previously uncharacterized lncRNA, was found to be located in both the cytoplasm and the nucleus via fluorescence in situ hybridization assay. In addition, lncRNA15691 upregulated the expression of CCR9 and was involved in T-cell acute lymphoblastic leukemia cell invasion. In vivo experiments showed that lncRNA15691 promoted leukemia cell homing/infiltration into the bone marrow, blood, and spleen, whereas the CCR9 ligand, CCL25, augmented the extramedullary infiltration of CCR9low leukemia cells overexpressing lncRNA15691 into blood, spleen, and liver. Subsequently, RNA protein pull-down assays, coupled with liquid chromatography-tandem mass spectrometry, were used to uncover potential lncRNA15691-interacting proteins, which were then validated by RNA immunoprecipitation. These mechanistic studies revealed that lncRNA15691 upregulated CCR9 expression via directly binding to and stabilizing MATR3 by inhibiting its nuclear degradation mediated by PKA. Collectively, our study revealed a novel mechanism of regulating CCR9 expression and implicated lncRNA15691 as a potential novel biomarker for T-cell acute lymphoblastic leukemia infiltration.

中文翻译：

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LncRNA15691 通过增加 MATR3 稳定性上调 CCR9 来促进 T-ALL 浸润。

我们之前的研究表明，CCR9 在 T 细胞急性淋巴细胞白血病进展的几个方面发挥着重要作用，并且 CCR9 是一个潜在的治疗靶点。然而，调节 CCR9 表达的潜在机制仍未完全了解。在这项研究中，临床样本的生物信息学分析和验证显示 lncRNA15691 与 CCR9 mRNA 表达呈正相关，并且在 T 细胞急性淋巴细胞白血病样本和 CCR9high T 细胞急性淋巴细胞白血病细胞系中显着上调。LncRNA15691 是一种先前未表征的 lncRNA，通过荧光原位杂交测定被发现位于细胞质和细胞核中。此外，lncRNA15691上调CCR9的表达并参与T细胞急性淋巴细胞白血病细胞侵袭。体内实验表明，lncRNA15691 促进白血病细胞归巢/浸润到骨髓、血液和脾脏中，而 CCR9 配体 CCL25 增强了过度表达 lncRNA15691 的 CCR9low 白血病细胞向血液、脾脏和肝脏中的髓外浸润。随后，RNA 蛋白下拉分析与液相色谱-串联质谱法相结合，用于发现潜在的 lncRNA15691 相互作用蛋白，然后通过 RNA 免疫沉淀对其进行验证。这些机制研究表明，lncRNA15691 通过直接结合并稳定 MATR3，抑制其由 PKA 介导的核降解，从而上调 CCR9 的表达。总的来说，