Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs

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. Prior stimulation with bacterial and viral products followed by the loss of Tet2 remodels the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Trif-Plk-Elf1 axis and drives the development of MDS.

Automated summary

Prior infection stress and loss of Tet2 gene can remodel the transcriptional and epigenetic landscapes and cellular functions in hematopoietic stem cells (HSCs) via the Trif-Plk-Elf1 axis and drive the development of myelodysplastic syndrome (MDS). Pharmacological inhibition of Plk function or knockdown of Elf1 expression can prevent epigenetic remodeling in HSCs and alleviate clonogenicity enhancement and impaired erythropoiesis. Additionally, the Elf1-target signature is significantly enriched in MDS HSPCs in humans.