PDF(Pubmed)
Abstract：
Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic hematopoietic disorders characterized by cytopenia in peripheral blood due to ineffective hematopoiesis and normo- or hypercellularity and morphologic dysplasia in bone marrow (BM). An inflammatory BM microenvironment and programmed cell death of hematopoietic stem/progenitor cells (HSPCs) are thought to be the major causes of ineffective hematopoiesis in MDS. Pyroptosis, apoptosis and necroptosis (collectively, PANoptosis) are observed in BM tissues of MDS patients, suggesting an important role of PANoptosis in MDS pathogenesis. Caspase 8 (Casp8) is a master regulator of PANoptosis, which is downregulated in HSPCs from most MDS patients and abnormally spliced in HSPCs from MDS patients with SRSF2 mutation. To study the role of PANoptosis in hematopoiesis, we generated inducible Casp8 knockout mice (Casp8-/-). Mx1-Cre-Casp8-/- mice died of BM failure within 10 days of polyI:C injections due to depletion of HSPCs. Rosa-ERT2Cre-Casp8-/- mice are healthy without significant changes in BM hematopoiesis within the first 1.5 months after Casp8 deletion. Such mice developed BM failure upon infection or low dose polyI:C/LPS injections due to the hypersensitivity of Casp8-/- HSPCs to infection or inflammation-induced necroptosis which can be prevented by Ripk3 deletion. However, impaired self-renewal capacity of Casp8-/- HSPCs cannot be rescued by Ripk3 deletion due to activation of Ripk1-Tbk1 signaling. Most importantly, mice transplanted with Casp8-/- BM cells developed MDS-like disease within 4 months of transplantation as demonstrated by anemia, thrombocytopenia and myelodysplasia. Our study suggests an essential role for a balance in Casp8, Ripk3-Mlkl and Ripk1-Tbk1 activities in the regulation of survival and self-renewal of HSPCs, the disruption of which induces inflammation and BM failure, resulting in MDS-like disease.
摘要：
骨髓增生异常综合征（MDS）是一组异质性的白血病前造血系统疾病，其特征是由于无效的造血作用而导致外周血中的血细胞减少以及骨髓（BM）中的正常或高细胞和形态发育异常。炎性BM微环境和造血干/祖细胞（HSPC）的程序性细胞死亡被认为是MDS中无效造血的主要原因。焦亡,凋亡和坏死(统称，在MDS患者的BM组织中观察到PANoptosis），提示PANoptosis在MDS发病机制中的重要作用。半胱天冬酶8(Casp8)是PANoptosis的主要调节因子,在大多数MDS患者的HSPCs中下调，在具有SRSF2突变的MDS患者的HSPCs中异常剪接。为了研究PANoptosis在造血中的作用，我们产生了诱导型Casp8敲除小鼠(Casp8-/-)。Mx1-Cre-Casp8-/-小鼠在polyI:C注射的10天内死于BM失败,这是由于HSPC的消耗。Rosa-ERT2Cre-Casp8-/-小鼠是健康的,在Casp8缺失后的前1.5个月内BM造血没有显著变化。由于Casp8-/-HSPC对感染或炎症诱导的坏死的超敏反应,这类小鼠在感染或低剂量polyI:C/LPS注射时出现BM衰竭,这可以通过Ripk3缺失来预防。然而,由于Ripk1-Tbk1信号的激活，无法通过Ripk3删除来挽救Casp8-/-HSPC的自我更新能力受损。最重要的是,用Casp8-/-BM细胞移植的小鼠在移植后4个月内出现MDS样疾病，如贫血所示，血小板减少和骨髓增生异常。我们的研究表明，Casp8，Ripk3-Mlkl和Ripk1-Tbk1活性的平衡在调节HSPCs的生存和自我更新中起着至关重要的作用。其破坏会导致炎症和BM衰竭，导致MDS样疾病。
