Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University , Kumamoto, Japan.
Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
J Exp Med. 2023 Jul 3;220(7). doi: 10.1084/jem.20220962. Epub 2023 Apr 18.
Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. We herein demonstrated that a prior stimulation with bacterial and viral products followed by loss of the Tet2 gene facilitated the development of MDS via up-regulating the target genes of the Elf1 transcription factor and remodeling the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Trif signaling but did not increase genomic mutations. The pharmacological inhibition of Plk function or the knockdown of Elf1 expression was sufficient to prevent the epigenetic remodeling in HSCs and diminish the enhanced clonogenicity and the impaired erythropoiesis. Moreover, this Elf1-target signature was significantly enriched in MDS HSPCs in humans. Therefore, prior infection stress and the acquisition of a driver mutation remodeled the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Trif-Plk-Elf1 axis, which promoted the development of MDS.
异常的固有免疫信号在骨髓增生异常综合征（MDS）造血干细胞/祖细胞（HSPCs）中被认为是 MDS 发展的驱动因素。本文证明，先前的细菌和病毒产物刺激，随后 Tet2 基因缺失，通过上调 Elf1 转录因子的靶基因，并以依赖于 Toll 样受体 3/4-TRIF 信号下游的 Polo 样激酶（Plk）的方式重塑造血干细胞（HSCs）中的表观基因组，从而促进 MDS 的发展，但不会增加基因组突变。Plk 功能的药理学抑制或 Elf1 表达的敲低足以防止 HSCs 中的表观遗传重塑，并减少增强的集落形成能力和受损的红细胞生成。此外，该 Elf1 靶标特征在人类 MDS HSPCs 中显著富集。因此，先前的感染应激和获得驱动突变通过 Trif-Plk-Elf1 轴重塑了 HSCs 的转录和表观遗传景观以及细胞功能，从而促进了 MDS 的发展。
