Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic Kras^G12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras^G12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras^G12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras^G12D-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.

致癌Ras突变发生在各种白血病中。目前尚不清楚，除了通过持续的 RAS/MEK/ERK 信号传导产生的直接转化作用之外，KRAS 的炎症相关作用是否会导致该疾病。在这里，我们确定了小鼠和人类细胞中致癌性Kras ^G12D和 NLRP3 炎性体激活之间的功能联系。在造血系统中表达活性Kras ^{G12D 的}小鼠出现骨髓增殖和血细胞减少，而在造血系统中缺乏 NLRP3 的Kras ^{G12D小鼠中则相反。}治疗性 IL-1 受体阻断或 NLRP3 抑制可减少骨髓增殖并改善造血功能。从机制上讲，Kras ^G12D -RAC1 激活会诱导活性氧 (ROS) 产生，从而导致 NLRP3 炎症小体激活。与我们在小鼠中的观察结果一致，患者来源的髓系白血病细胞表现出 KRAS/RAC1/ROS/NLRP3/IL-1β 轴活性。我们的研究结果表明，致癌 KRAS 不仅通过其典型的致癌驱动功能发挥作用，而且还增强促炎性 RAC1/ROS/NLRP3/IL-1β 轴的激活。这为基于通过 NLRP3 阻断进行免疫调节的 KRAS 突变骨髓恶性肿瘤的治疗方法铺平了道路。