Exposure to Microbial Products Followed by Loss of Tet2 Promotes Myelodysplastic Syndrome Via Remodeling HSCs

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2023 Apr 18

PMID 37071125

Authors

Takako Yokomizo-Nakano

Ai Hamashima

Sho Kubota

Jie Bai

Supannika Sorin

Yuqi Sun

Kenta Kikuchi

Mihoko Iimori

Mariko Morii

Akinori Kanai

Atsushi Iwama

Gang Huang

Daisuke Kurotaki

Hitoshi Takizawa

Hirotaka Matsui

Goro Sashida

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions.

Kubota S, Sun Y, Morii M, Bai J, Ideue T, Hirayama M EMBO J. 2024; 43(13):2661-2684.

PMID: 38811851 PMC: 11217491. DOI: 10.1038/s44318-024-00122-4.

Stem cell regulation and dynamics in myeloid malignancies.

Sashida G Int J Hematol. 2023; 117(6):789-790.

PMID: 37191835 DOI: 10.1007/s12185-023-03615-w.

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