T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric malignancy that arises from the transformation of immature T-cell progenitors and has no definitive cure. Notch signaling governs many steps of T cell development and its dysregulation represents the most common causative event in the pathogenesis of T-ALL. The activation of canonical NF-κB pathway has been described as a critical downstream mediator of Notch oncogenic functions, through the sustaining of tumor cell survival and growth. The potential role of Notch/NF-κB partnership is also emerging in the generation and function of regulatory T cells (Tregs) in the context of cancer. However, little is known about the effects of combined mutations of Notch and NF-κB in regulating immune-environment and progression of T-ALL. To shed light on the topics above we generated double-mutant mice, harboring conventional knock-out mutation of NF-κB1/p50 on the genetic background of a transgenic model of Notch-dependent T-ALL. The immunophenotyping of double-mutant mice demonstrates that NF-κB1 deletion inhibits the progression of T-ALL and strongly modifies immune-environment of the disease. Double-mutant mice display indeed a dramatic reduction of pre-leukemic CD4+CD8+ (DP) T cells and regulatory T cells (Tregs) and, concurrently, the rising of an aggressive myeloproliferative trait with a massive expansion of CD11b+Gr-1+ cells in the periphery, and an accumulation of the granulocyte/monocyte progenitors in the bone-marrow. Interestingly, double-mutant T cells are able to improve the growth of CD11b+Gr-1+ cells in vitro, and, more importantly, the in vivo depletion of T cells in double-mutant mice significantly reduces the expansion of myeloid compartment. Our results strongly suggest that the myeloproliferative trait observed in double-mutant mice may depend on non-cell-autonomous mechanism/s driven by T cells. Moreover, we demonstrate that the reduction of CD4+CD8+ (DP) T cells and Tregs in double-mutant mice relies on a significant enhancement of their apoptotic rate. In conclusion, double-mutant mice may represent a useful model to deepen the knowledge of the consequences on T-ALL immune-environment of modulating Notch/NF-κB relationships in tumor cells. More importantly, information derived from these studies may help in the refinement of multitarget therapies for the disease.

中文翻译：

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NF-κB1调节免疫环境和Notch依赖性T细胞急性淋巴细胞白血病的结果。

T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性的儿科恶性肿瘤，由未成熟T细胞祖细胞的转化引起，尚无确切的治疗方法。Notch信号控制着T细胞发育的许多步骤，其失调代表了T-ALL发病机理中最常见的致病事件。通过维持肿瘤细胞的存活和生长，经典的NF-κB途径的激活被描述为Notch致癌功能的关键下游介质。在癌症的情况下，Notch /NF-κB伙伴关系的潜在作用也在调节性T细胞（Tregs）的产生和功能中出现。但是，关于Notch和NF-κB联合突变对调节免疫环境和T-ALL进程的影响知之甚少。为了阐明上述主题，我们生成了双突变小鼠，其在Notch依赖的T-ALL转基因模型的遗传背景中带有NF-κB1/ p50的常规​​敲除突变。双突变小鼠的免疫表型研究表明，NF-κB1缺失抑制了T-ALL的进程，并强烈改变了该疾病的免疫环境。双突变小鼠确实显示了白血病前CD4 + CD8 +（DP）T细胞和调节性T细胞（Tregs）的显着减少，同时，侵略性骨髓增生性状的出现以及CD11b + Gr-1 +的大量扩增外周的细胞，以及骨髓中粒细胞/单核细胞祖细胞的积累。有趣的是，双突变T细胞能够在体外改善CD11b + Gr-1 +细胞的生长，更重要的是，双突变小鼠体内T细胞的体内消耗显着降低了髓样区室的扩增。我们的结果强烈表明，在双突变小鼠中观察到的骨髓增生性状可能取决于T细胞驱动的非细胞自主机制。而且，我们证明了双突变小鼠中CD4 + CD8 +（DP）T细胞和Treg的减少依赖于其凋亡率的显着提高。总之，双突变小鼠可能代表了一个有用的模型，可以加深对调节肿瘤细胞中Notch /NF-κB关系对T-ALL免疫环境的影响的认识。更重要的是，从这些研究中获得的信息可能有助于改善该疾病的多靶点疗法。我们的结果强烈表明，在双突变小鼠中观察到的骨髓增生性状可能取决于T细胞驱动的非细胞自主机制。而且，我们证明了双突变小鼠中CD4 + CD8 +（DP）T细胞和Treg的减少依赖于其凋亡率的显着提高。总之，双突变小鼠可能代表了一个有用的模型，可以加深对调节肿瘤细胞中Notch /NF-κB关系对T-ALL免疫环境的影响的认识。更重要的是，从这些研究中获得的信息可能有助于改善该疾病的多靶点疗法。我们的结果强烈表明，在双突变小鼠中观察到的骨髓增生性状可能取决于T细胞驱动的非细胞自主机制。而且，我们证明了双突变小鼠中CD4 + CD8 +（DP）T细胞和Treg的减少依赖于其凋亡率的显着提高。总之，双突变小鼠可能代表了一个有用的模型，可以加深对调节肿瘤细胞中Notch /NF-κB关系对T-ALL免疫环境的影响的认识。更重要的是，从这些研究中获得的信息可能有助于改善该疾病的多靶点疗法。我们证明，双突变小鼠中CD4 + CD8 +（DP）T细胞和Treg的减少依赖于其凋亡率的显着提高。总之，双突变小鼠可能代表了一个有用的模型，可以加深对调节肿瘤细胞中Notch /NF-κB关系对T-ALL免疫环境的影响的认识。更重要的是，从这些研究中获得的信息可能有助于改善该疾病的多靶点疗法。我们证明，双突变小鼠中CD4 + CD8 +（DP）T细胞和Treg的减少依赖于其凋亡率的显着提高。总之，双突变小鼠可能代表了一个有用的模型，可以加深对调节肿瘤细胞中Notch /NF-κB关系对T-ALL免疫环境的影响的认识。更重要的是，从这些研究中获得的信息可能有助于改善该疾病的多靶点疗法。