Inducible Sbds deletion impairs bone marrow niche capacity to engraft donor bone marrow after transplantation

Abstract

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited bone marrow failure syndromes (iBMFS). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes bone marrow dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC following HSCT, a hypothesis that could explain morbidity seen after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have additionally identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and that are accentuated or develop specifically following myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets including mesenchymal lineage cells, macrophages and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation, and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.

Reduced proliferation of bone marrow MSC after allogeneic stem cell transplantation is associated with clinical outcome

“…Recent studies in murine models of alloSCT show that the recipient BM niche determines engraftment of donor hematopoiesis. 3 This is in agreement with the well-known relevance of the BM niche in humans for maintaining the hematopoietic stem cell (HSC) population and controlling their differentiation. 4 …”

“… 15 Consequently in murine alloSCT models, damage of MSC results in reduced hematopoietic engraftment. 3 Cytotoxic and inflammatory processes in the context of alloSCT may lead to changes in BM niche and specifically to alterations in BM-MSC thereby affecting donor hematopoiesis and the associated clinical outcome. Therefore, a better understanding of the molecular underpinnings of post-alloSCT niche function and its effects on graft functionality is warranted.…”

Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants

“…A role for mesenchymal cells in altering the BM microenvironment has been advanced and may contribute to dysmyelopoiesis or leukemogenesis. [61][62][63] Increased apoptosis was observed in SDS-derived BM in combination with p53 overexpression. 64,65 In studies of human cells, SDS patient cells were hypersensitive to low doses of actinomycin D, an inhibitor of rRNA transcription and its administration abolished nucleolar localization of SBDS.…”

Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman–Diamond syndrome cells

“…drug. Since both dysregulation of TP53 and stroma 40,41 may contribute to leukaemogenesis in SDS, ataluren might also reduce the risk of leukaemic progression in SDS patients. Overall, our study suggests that ataluren can be a promising personalized medicine approach for SDS patients carrying nonsense mutations.…”

“…Although OBs respond to higher doses of ataluren compared to haematopoietic cells, ataluren‐dependent improvement of SBDS levels in mesenchymal cells from bone matrix may further justify the clinical development of this drug. Since both dysregulation of TP53 and stroma 40,41 may contribute to leukaemogenesis in SDS, ataluren might also reduce the risk of leukaemic progression in SDS patients. Overall, our study suggests that ataluren can be a promising personalized medicine approach for SDS patients carrying nonsense mutations.…”