Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs

Abstract

Myelodysplastic syndromes (MDS) have long been considered hematopoietic-cell autonomous disorders in which disease initiation and progression is exclusively driven by hematopoietic cell intrinsic genetic events. Recent experimental findings have challenged this view, implicating mesenchymal elements in the bone marrow microenvironment in disease pathogenesis. Specifically, genetic perturbation of mesenchymal cells has the ability to induce MDS and acute myeloid leukemia, establishing an experimental concept of ‘niche-induced’ oncogenesis. 1 , 2 Alternatively, primary alterations in hematopoietic cells have the ability to alter mesenchymal niche components, such that niche cells facilitate disease propagation in the context of xenograft transplantation. 3 Together, these observations challenge the view that ineffective hematopoiesis and leukemic progression is exclusively driven by hematopoietic-cell autonomous events in human MDS. Translation of experimental findings to human disease is complicated by a lack of insight in the molecular wiring of primary, non-expanded mesenchymal cells in MDS. Insights into the biology of mesenchymal elements in human MDS and other hematopoietic disorders thus far have been derived from studies investigating ex vivo -expanded mesenchymal cells derived from the diseased bone marrow. The hierarchic, biologic and molecular relationship between these ex vivo -expanded cells and their in situ counterparts, however, has remained largely unknown. Here we describe massive parallel transcriptome sequencing of prospectively isolated mesenchymal elements from human low-risk MDS (LR-MDS), revealing a common molecular signature, distinct from both normal and ex vivo -expanded cells, characterized by cellular stress and upregulation of genes encoding inflammation-associated secreted factors with established inhibitory effects on hematopoiesis.