Alterations within the Osteo-Hematopoietic Niche in MDS and their Therapeutic Implications

Abstract

Hematopoietic and mesenchymal stem and progenitor cells are organized in the osteo-hematopoietic niche, a complex microenvironment ensuring self-renewal and differentiation. Perturbations of the niche architecture, the mutual cellular interactions and signaling pathways disrupt tissue homeostasis resulting in cytopenia and malignant diseases such as myelodysplastic syndromes (MDS), supporting the concept of niche-induced oncogenesis. Analyzing the available treatment options for patients harboring MDS, it becomes evident that many of them specifically modify components of the stem cell niche. Hereby especially compounds inhibiting the TGF-β superfamily seem to represent a promising novel approach for patients with anemia as a result of ineffective erythropoiesis. Moreover, apart from affecting tumorigenesis, these drugs appear to influence bone structure and function as well as hematopoiesis in elderly MDS patients with a disturbed microarchitecture of the bone marrow. In the present review we will dissect the contribution of components of the stem cell niche for the pathogenesis of MDS and discuss current therapeutic strategies targeting components of the niche, focusing on the modulation of TGF-β signaling.

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

“…We expect that elucidation of the transcriptome of highly purified mesenchymal elements in MDS will thus be a valuable resource to the community, instructing the validation and discovery of novel pathophysiologic factors and putative therapeutic targets. 11 …”

Beyond the Niche: Myelodysplastic Syndrome Topobiology in the Laboratory and in the Clinic

“…There has been a lot of attention paid to the role of MSCs in normal and dysplastic/leukemic hematopoiesis, in both mouse and human [ 86 , 87 , 88 , 89 ], The first papers that characterized MSCs in the setting of MDS by morphology, immunophenotype and differentiation potential were published in 2005 [ 90 ] and since, more than 80 papers have been published in this field ( Table 1 ).The first finding was related to the chromosomal abnormalities present in MSCs. In this regard, Flores-Figueroa et al , first described that MSCs from MDS patients harbor chromosomal abnormalities in 55.5% of the patients [ 90 ]; Blau et al corroborated this finding in 44% of their cohort [ 91 ].…”

Introductory Chapter: Myelodysplastic Syndromes

“…Two hypomethylating agents (azacitidine and decitabine) inhibit DNA methyltransferases 3A and 3B and reverse the aberrant methylation involved in MDS progression to AML. The development of novel therapeutic strategies in MDS is dependent on recent advances in the molecular pathogenesis of MDS [6,16,[28][29][30][31][32][33][34][35][36][37][38][39]. Various combination therapies in MDS are also intensively studied [27,40,41].…”