The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2−/−γc−/− MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.
慢性淋巴细胞白血病（CLL）的发生和发展取决于遗传异常及免疫抑制微环境。我们探讨了遗传驱动因素可能导致免疫细胞失调进而形成促肿瘤微环境的可能性。我们基于Rag2−/−γc−/− MEC1异种移植模型，在白血病进展过程中对编码和非编码RNA（ncRNA）进行了转录组分析。发现在白血病小鼠的单核细胞/巨噬细胞中，*DLEU2/miR-16*基因座表达下调。为验证该基因簇在肿瘤免疫微环境中的作用，我们建立了一种同时模拟hTCL1过表达与编码*DLEU2/miR-15a/miR-16-1*基因簇的最小缺失区（MDR）种系缺失的小鼠模型。该模型提供了一种创新且更快速的CLL研究体系，其中单核细胞分化和巨噬细胞极化加剧，且T细胞功能失调。MDR缺失与小鼠CLL细胞及免疫细胞中BCL2、PD1/PD-L1等预测靶蛋白水平呈负相关。miR-15a/miR-16-1与靶蛋白的负相关关系已在患者来源的免疫细胞中得到证实。强制表达miR-16-1可干扰单核细胞向肿瘤相关巨噬细胞的分化，表明特定ncRNA驱动了非恶性免疫细胞的促肿瘤表型。
肿瘤(癌症)患者之家