PDF(Pubmed)
Abstract：
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 KRASG12D 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.
摘要：
慢性粒单核细胞白血病（CMML）通常与大鼠肉瘤基因（RAS）的突变有关，导致预后更差。RAS突变导致活性RAS-GTP蛋白，有利于骨髓细胞增殖和存活，并诱导NLRP3炎性体与含有caspase募集结构域（ASC）的凋亡相关斑点样蛋白，促进caspase-1的激活和白细胞介素（IL）-1β的释放。这里,我们报告,在一组KRAS突变的CMML患者中，单核细胞中NLRP3炎性体的组成型激活，ASC寡聚化和IL-1β释放证明，以及特定的炎性细胞因子特征。使用IL-1受体阻滞剂anakinra治疗具有KRASG12D突变的CMML患者会抑制NLRP3炎性体激活，减少单核细胞计数,改善病人的临床状况,能够进行干细胞移植。这揭示了RAS突变的CMML患者的基础炎性体激活，并提示了NLRP3和IL-1阻断剂的潜在治疗应用。
