Myelodysplasia is in the niche: novel concepts and emerging therapies

Abstract

Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of ‘osteohematology' as an emerging research field in MDS and outline clinical implications.

The hematopoietic stem cell niche in homeostasis and disease

“…Much data from both murine models and primary human samples suggest a role for bone marrow stromal cell populations in the pathogenesis of MDS [106][107][108] (also reviewed in Balderman and Calvi 109 and Bulycheva et al 110 )…”

Origin of stem cells in the BM niche: new clues from mastocytosis

“…A crucial issue for future studies will be to determine what type of BCR signaling inhibitor would be most appropriate for patients belonging to each of the 2 DLBCL subsets with an activated BCR pathway. Based on the results of this study and the study of Chen et al, 5 both SYK and PI3K inhibitors would be expected to be active in BCRdependent DLBCL, independently of the mechanism that activates the BCR pathway. Although clinical data are scarce, the SYK inhibitor fostamatinib, which is the prodrug of R406, has already shown clinical activity in patients with DLBCL, with 22% (5/23) of the treated patients responding to treatment.…”

Zebrafish embryonic stromal trunk (ZEST) cells support hematopoietic stem and progenitor cell (HSPC) proliferation, survival, and differentiation

“…Importantly, stromal cells are useful for understanding not only normal hematopoiesis, but also the effect of the hematopoietic niche on hematologic disease development 53 . Other groups created zebrafish hematopoietic supportive mesenchymal stem cell lines from sdf1 :DsRed transgenic animals 54 , allowing investigation of the hematopoietic niche, positing the zebrafish as a useful model system to study niche/HSPC interactions.…”