VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe, inflammatory syndrome resulting from mutated UBA1 leading to hematopoietic stem cells (HSC) expansion. Although UBA1 -mutant HSC show complex phenotypes including proteostasis defects, sustained inflammation and clonal expansion of myeloid biased progeny, the pathogenic mechanisms at the HSC level are unknown from these gene-centric studies alone. By focussing on the non-coding genome and using advanced functional genetic methods, we found that VEXAS HSC, compared to controls, had altered expression of individual transposable elements (TE) and are key regulators of VEXAS pathogenesis. Locus-specific TE quantification identified two L1 elements, L1-10 and L1-15, active in both normal and VEXAS HSC that drive myeloid commitment by co-opting SPI1 and IRF1 transcription factors (TF) via networks common to other myeloid-biased conditions. Lipid nanoparticle (LNP)-mediated CRISPRi of L1-10 and L1-15 in UBA1 -mutant HSC also caused reversion of VEXAS-associated functional phenotypes in vitro and in vivo . Functionally, pharmacologic inhibition of UBA1 with TAK-243 led to L1-10 and L1-15 RNA accumulation, while enhancement of UBA1 activity with Auranofin reversed this effect. Our study provides direct evidence that VEXAS-specific TE govern HSC clonal dominance, thereby uncovering a regulatory axis underlying HSC biology and disease mechanisms, opening a therapeutic strategy directed towards the repetitive genome.