WES data in project that prior infection stresses activate Elf1 and remodel epigenome in hematopoietic stem cell to develop myelodysplastic syndrome

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.