Effect of order of infection stresses and Tet2 deletion to drive transformation of myelodysplastic syndrome. Mus musculus

ATA-seq-data of underwritten project. Aberrant inflammatory signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) due to environmental stresses including infections and normal aging has been implicated as a driver of the development of MDS. Here, we demonstrate that the earlier short-term stimulation of both lipopolysaccharides (LPS) and polyinosinic:polycytidylic acid (pIpC), mimics of bacterial and viral infections, facilitated the development of MDS subsequently deleted Tet2 gene in the bone marrow in wild-type recipients, compared to na?ve Tet2-deficient cells; however, the reverse order of Tet2 deletion and the same dosage stimulation of LPS/pIpC in Tet2-deficient bone marrow cells in recipient mice did not. Consistently, normal aging in wild-type background enhanced the competitive repopulating capacity of HSPCs and myeloid cell production upon the deletion of Tet2 at two years age in mice, indicating that the earlier infection and aging stresses in wild-type background and the subsequent driver mutation facilitated the development of MDS. The earlier stimulation of LPC/pIpC and the Tet2 deletion augmented expression of genes involved in innate immune responses and Elf1 transcription factor and altered chromatin accessibility in pre-MDS stem cells dependent on Polo-like kinases downstream of the Tlr3/4-Myd88/Trif signaling, resulting in the development of progressive MDS presenting impaired differentiation and enhanced repopulation of HSPCs. Moreover, this LPS/pIpC-induced Elf1-target signature was significantly enriched in non-5q- MDS HSPCs in patients. Thus, the order of the infection stresses and the acquisition of driver mutation influenced the transcriptional and epigenetic landscapes, cellular functions and clonal expansion of MDS.