BioProject

Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. More...

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 an prior earlier short-term stimulation with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (pIpC), which mimic bacterial and viral infections, respectively, facilitated the development of MDS following the deletion of Tet2 gene in bone marrow cells. The priorearlier stimulation with LPS/pIpC and the subsequent deletion of Tet2 augmented the up-regulation of the target genes of the Elf1 transcription factor and remodeled the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Myd88/Trif signaling. The pharmacological inhibition of Plk function or the knockdown of Elf1 expression was sufficient to prevent the stimulation-induced epigenetic remodeling in HSCs and diminish the enhanced clonogenicity and the impaired erythropoiesis. Moreover, this LPS/pIpC stimulation-induced Elf1-target signature was significantly enriched in MDS HSPCs in humans. Therefore, the priorearlier infection stresses and the acquisition of a driver mutation remodeled the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Myd88/Trif-Plk-Elf1 axis and facilitated the development of MDS. Less...