Notch hyperactivation dominates T-cell acute lymphoblastic leukemia development, but the mechanisms underlying "pre-leukemic" cell dissemination are still unclear. Here we describe how deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4⁺CD8⁺ thymocytes, possibly contributing to "pre-leukemic" cell propagation, early in disease progression. In transgenic mice overexpressing the constitutively active Notch3 intracellular domain, we detect the progressive increase in circulating blood and bone marrow of CD4⁺CD8⁺ cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4⁺CD8⁺ cells reveals their competence in infiltrating spleen and bone marrow of immunocompromised recipient mice. We also show that CXCR4 surface expression is central to the migratory ability of CD4⁺CD8⁺ cells and such an expression is regulated by Notch3 through β-arrestin in human leukemia cells. De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4⁺CD8⁺ cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4⁺CD8⁺ cells in young Notch3 transgenic mice. Therefore, our data suggest that combined therapies precociously counteracting intrathymic Notch3/CXCR4 crosstalk may prevent dissemination of "pre-leukemic" CD4⁺CD8⁺ cells, by a "thymus-autonomous" mechanism.

中文翻译：

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胸腺内Notch3和CXCR4组合相互作用促进T细胞白血病的传播。

Notch过度活化在T细胞急性淋巴细胞白血病的发展中起着主导作用，但是“白血病前”细胞传播的机制尚不清楚。在这里，我们描述了失调的Notch3信号如何在疾病进展的早期阶段增强CXCR4细胞表面表达和CD4 ⁺ CD8 ⁺胸腺细胞的迁移能力，可能有助于“白血病前期”细胞增殖。在过表达组成型活性Notch3细胞内结构域的转基因小鼠中，我们检测到CD4 ⁺ CD8 ⁺细胞的循环血液和骨髓中的进行性增加，其特征在于Notch3和CXCR4的表面表达高且结合在一起。我们首次报告了这种CD4 ⁺ CD8的移植⁺细胞揭示了它们在免疫受损受体小鼠的脾脏和骨髓浸润中的能力。我们还显示，CXCR4表面表达对于CD4 ⁺ CD8 ⁺细胞的迁移能力至关重要，并且这种表达受Notch3通过人白血病细胞中β-arrestin的调控。从头开始，我们提出通过增强CXCR4依赖性迁移来激活Notch3信号，可促进白血病早期从胸腺CD4 ⁺ CD8 ⁺细胞的异常出口。实际上，体内CXCR4拮抗作用可阻止此类CD4 ⁺ CD8 ^+的骨髓定植年轻的Notch3转基因小鼠体内的细胞。因此，我们的数据表明，通过“胸腺自发”机制，联合疗法能早日抵消胸腺内Notch3 / CXCR4的串扰，可以阻止“白血病前” CD4 ⁺ CD8 ⁺细胞的传播。