Differential sensitivity to LINE 1-induced damage contributes to the expansion of Tet2-deficient HSCs upon chronic inflammatory stress

Abstract

Chronic inflammation disrupts hematopoietic stem cell (HSC) function and drives the expansion of TET2-mutated clones, fostering clonal hematopoiesis of indeterminate potential (CHIP). However, the molecular mechanisms linking inflammation to these hematopoietic alterations remain poorly understood. Here, we uncover a pivotal role of transposable element (TE) derepression, specifically of the most recent LINE-1 (L1) elements, in mediating inflammation-induced HSC dysfunction. We show that chronic exposure to low-dose lipopolysaccharide (LPS) causes a loss of the heterochromatin mark H3K9me3 at L1s in wild-type (WT) HSCs, leading to L1 activation, DNA damage, and reduced clonogenic capacity. Remarkably, Tet2-/- HSCs are resistant to this LPS-induced L1 derepression and associated genomic instability. Furthermore, targeted degradation of L1 RNAs in WT HSCs diminishes the competitive advantage of Tet2-/- HSCs under chronic inflammatory conditions both in vitro and in vivo. These findings reveal epigenetic control of L1 elements as a previously unrecognized mechanism that links chronic inflammation to HSC impairment and clonal expansion of Tet2-mutant cells. This work highlights TE regulation as a critical determinant of hematopoietic fitness and clonal evolution under inflammatory stress.