Toll-like receptor and cytokine expression throughout the bone marrow differs between patients with low- and high-risk myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, the pathogenesis of which involves enhanced immune signaling that promotes or selects for mutant hematopoietic stem and progenitor cells (HSPCs). In particular, toll-like receptor (TLR) expression and signaling are enhanced in MDS, and their inhibition is an attractive therapeutic strategy. Although prior studies have reported increased expression of TLR2 and its binding partners TLR1 and TLR6 in the CD34+ cells of patients with MDS (especially those with low-risk disease), TLR expression in other cell types throughout the bone marrow is largely unknown. To address this, we used mass cytometry to assess the expression of TLR1, TLR2, and TLR6 and cytokines in the bone marrow hematopoietic cells of six low/intermediate-risk and six high-risk unmatched MDS bone marrow samples, as well as healthy controls, both at baseline and in response to TLR agonists. We observed several consistent differences between the groups. Most notably, TLR expression was upregulated in multiple cell populations in the low/intermediate-risk, but not high-risk, patients. In addition, many cytokines, including interleukin-6, interleukin-8, tumor necrosis factor α, transforming growth factor β, macrophage inflammatory protein 1β, and granzyme B, were highly expressed from various cell types in low/intermediate-risk patients. However, these same cytokines, with the exception of transforming growth factor β, were expressed at lower levels in high-risk MDS. Together, these findings highlight the differential role of inflammation, and specifically TLR expression, in low/intermediate- versus high-risk MDS, and suggest that elevated TLR expression and cytokine production in multiple cell types likely influences the pathogenesis of MDS in lower-risk patients.