<br>BACH2介导的CD28和CD40LG轴有助于T细胞淋巴细胞白血病的发病机制和进展,Cell Death & Disease

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BACH2介导的CD28和CD40LG轴有助于T细胞淋巴细胞白血病的发病机制和进展
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-01-17 , DOI: 10.1038/s41419-024-06453-8
Min Feng ₁ , Bailing Zhang _{2,

3,

4} , Guilan Li ₁ , Yan Yang ₁ , Jiangyuan Liu ₁ , Ziting Zhang ₁ , Bing Zhou _{2,

3,

4} , Han Zhang ₁

Affiliation

摘要T细胞急性淋巴细胞白血病（T-ALL）是ALL的一种侵袭性亚型，具有高度异质性和不利的临床特征。尽管对 T-ALL 的遗传和表观遗传景观有了更深入的了解，但驱动恶性 T 细胞发育的分子机制仍不清楚。 BTB 和 CNC 同源 2 (BACH2) 是一种淋巴特异性转录抑制因子，被认为是 B 细胞恶性肿瘤中的肿瘤抑制因子，但对其在 T-ALL 中的功能和调控网络知之甚少。在这里我们发现了极低的水平巴赫2 T-ALL 临床样本和细胞系与正常 T 细胞相比。 T-ALL细胞中BACH2的过度表达不仅诱导细胞生长迟缓，而且抑制异种移植物中的癌症进展和浸润。进一步的 RNA 测序 (RNA-seq) 分析揭示了 BACH2 过表达后 T-ALL 细胞的防御和免疫反应调节发生了显着变化。引人注目的是，T 细胞上的两种重要刺激分子 CD28 和 CD40LG 首次被确定为 T-ALL 细胞中 BACH2 抑制的新下游靶标。有趣的是，CD28和CD40LG对于T-ALL的存活都是不可或缺的，因为很大程度上或完全沉默CD28和CD40LG会导致细胞快速死亡，而部分敲低它们会导致细胞周期停滞并增强细胞凋亡。更重要的是，BACH2介导的CD28和CD40LG信号有助于T-ALL细胞的细胞迁移和扩散到骨髓，从而为T细胞恶性肿瘤中BACH2介导的肿瘤免疫调节添加了新的一层。

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BACH2-mediated CD28 and CD40LG axes contribute to pathogenesis and progression of T-cell lymphoblastic leukemia

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of ALL characterized by its high heterogeneity and unfavorable clinical features. Despite improved insights in genetic and epigenetic landscapes of T-ALL, the molecular mechanisms that drive malignant T-cell development remain unclear. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in B-cell malignancies, but little is known about its function and regulatory network in T-ALL. Here we found extremely low levels of BACH2 in T-ALL clinical samples and cell lines compared to normal T cells. Overexpression of BACH2 in T-ALL cells not only induced cell growth retardation but also inhibited cancer progression and infiltration in xenografts. Further RNA sequencing (RNA-seq) analysis revealed significant alterations in regulation of defense and immune responses in T-ALL cells upon BACH2 overexpression. Strikingly, CD28 and CD40LG, two essential stimulatory molecules on T cells, were for the first time identified as novel downstream targets repressed by BACH2 in T-ALL cells. Interestingly, both CD28 and CD40LG were indispensable for T-ALL survival, since largely or completely silencing CD28 and CD40LG led to rapid cell death, whereas partial knockdown of them resulted in cell-cycle arrest and enhanced apoptosis. More importantly, BACH2-mediated CD28 and CD40LG signals contributed to cell migration and dissemination of T-ALL cells to the bone marrow, thus adding a new layer to the BACH2-mediated tumor immunoregulation in T-cell malignancies.

更新日期：2024-01-17

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