Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain.
Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain; Hematology Department, Hospital Universitario Morales-Meseguer, Centro Regional de Hemodonación, Murcia, Spain; CIBERER CB15/00055 (U765), Murcia, Spain.
Cell Rep Med. 2023 Dec 19;4(12):101329. doi: 10.1016/j.xcrm.2023.101329.
Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRAS mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
慢性髓单核细胞白血病（CMML）常伴有大鼠肉瘤基因（RAS）突变，导致预后较差。RAS 突变导致活性 RAS-GTP 蛋白，有利于髓样细胞增殖和存活，并与凋亡相关斑点样蛋白（ASC）一起诱导 NLRP3 炎性体，促进 caspase-1 激活和白细胞介素（IL）-1β释放。在这里，我们报告了一组 KRAS 突变的 CMML 患者，其中单核细胞中的 NLRP3 炎性体持续激活，证据是 ASC 寡聚化和 IL-1β释放，以及特定的炎症细胞因子特征。使用白细胞介素 1 受体阻滞剂 anakinra 治疗 KRAS 突变的 CMML 患者可抑制 NLRP3 炎性体激活，减少单核细胞计数，并改善患者的临床状况，从而进行干细胞移植。这揭示了 RAS 突变的 CMML 患者中存在基础炎性体激活，并提示 NLRP3 和 IL-1 阻滞剂具有潜在的治疗应用。
