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^−/−γ_c^−/− 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和免疫抑制微环境。我们已经探索了遗传驱动因素可能导致塑造促肿瘤微环境的免疫细胞失调的可能性。我们在基于 Rag2 ^{- / -} γ_c^{- / -} MEC1 的异种移植模型中对白血病进展过程中的编码和非编码 RNA （ncRNA） 进行了转录组分析。DLEU2/miR-16 位点在白血病小鼠的单核细胞/巨噬细胞中被发现下调。为了验证该簇在肿瘤免疫微环境中的作用，我们生成了一个小鼠模型，该模型同时模拟 hTCL1 的过表达和编码 DLEU2/miR-15a/miR-16-1 簇的最小缺失区 （MDR） 的种系缺失。该模型提供了一种创新且更快的 CLL 系统，其中单核细胞分化和巨噬细胞极化加剧，T 细胞功能障碍。MDR 缺失与小鼠 CLL 细胞和免疫细胞上预测的靶蛋白（包括 BCL2 和 PD1/PD-L1）的水平呈负相关。miR-15a/miR-16-1 与靶蛋白的负相关已在患者来源的免疫细胞上得到证实。miR-16-1 的强制表达干扰单核细胞分化为肿瘤相关巨噬细胞，表明选定的 ncRNA 驱动非恶性免疫细胞的促肿瘤表型。