State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China;
School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
J Immunol. 2020 Jun 15;204(12):3400-3415. doi: 10.4049/jimmunol.2000230. Epub 2020 May 1.
Mixed-lineage leukemia 1 (MLL1), which exerts its H3K4 methyltransferase activity by interacting with WDR5, ASH2L, and RBBP5, plays a pivotal role in regulating hematopoietic stem cell homeostasis. Disrupting the integrity of MLL1-complex has been reported to be associated with acute leukemia. However, the exact role of MLL1-complex in myeloid cells is unknown. In this study, microarray analysis revealed that the core components of the Mll1-complex, Wdr5, Ash2l, and Mll1, were concurrently downregulated by tumor-secreted factors as well as GM-CSF + IL-6 during the accumulation and activation of murine myeloid-derived suppressor cells (MDSCs). These changes were further validated by quantitative RT-PCR and Western blotting both in vitro and in vivo. The expression levels of WDR5 and ASH2L were also significantly decreased in bone marrow MDSCs of lung cancer patients compared with that of healthy controls. Functionally, ectopic expression of Wdr5, Ash2l, and Mll1 (C terminus) reversed the accumulation and function of GM-CSF + IL-6-induced as well as tumor-cocultured polymorphonuclear MDSCs (PMN-MDSCs) by promoting them to differentiate into mature neutrophil-like cells. Mechanistically, GM-CSF + IL-6-activated Stat3 and Cebpβ synergistically induced the expression of miR-21a, miR-21b, and miR-181b, and thus inhibited the expression of Wdr5, Ash2l, and Mll1 by targeting to their 3' untranslated regions, respectively. Furthermore, knockdown of these microRNAs also suppressed the expansion and function of GM-CSF + IL-6-induced PMN-MDSCs. Taken together, our findings indicate that the Stat3/Cebpβ-miR-21a/b/181b-Mll1-complex axis may play a critical role in PMN-MDSC expansion, activation, and differentiation, and this axis may provide an effectively immunological therapeutic approach for patients with cancer or other immunological diseases.
混合谱系白血病 1（MLL1）通过与 WDR5、ASH2L 和 RBBP5 相互作用发挥其 H3K4 甲基转移酶活性，在调节造血干细胞稳态中发挥关键作用。据报道，破坏 MLL1 复合物的完整性与急性白血病有关。然而，MLL1 复合物在髓系细胞中的确切作用尚不清楚。在这项研究中，通过微阵列分析发现，Mll1 复合物的核心成分，Wdr5、Ash2l 和 Mll1，在小鼠髓源性抑制细胞（MDSC）的积累和激活过程中，被肿瘤分泌的因子以及 GM-CSF+IL-6 同时下调。这些变化在体外和体内通过定量 RT-PCR 和 Western blot 进一步验证。与健康对照组相比，肺癌患者骨髓 MDSC 中的 WDR5 和 ASH2L 表达水平也显著降低。功能上，Wdr5、Ash2l 和 Mll1（C 末端）的异位表达逆转了 GM-CSF+IL-6 诱导以及肿瘤共培养多形核 MDSC（PMN-MDSC）的积累和功能，促进它们分化为成熟的中性粒细胞样细胞。机制上，GM-CSF+IL-6 激活的 Stat3 和 Cebpβ 协同诱导 miR-21a、miR-21b 和 miR-181b 的表达，并分别通过靶向它们的 3'非翻译区抑制 Wdr5、Ash2l 和 Mll1 的表达。此外，这些 microRNA 的敲低也抑制了 GM-CSF+IL-6 诱导的 PMN-MDSC 的扩增和功能。总之，我们的研究结果表明，Stat3/Cebpβ-miR-21a/b/181b-Mll1 复合物轴可能在 PMN-MDSC 的扩增、激活和分化中发挥关键作用，该轴可能为癌症或其他免疫性疾病患者提供一种有效的免疫治疗方法。
