MYELODYSPLASTIC SYNDROMES BENEFIT FROM IRON-RESTRICTED BONE MARROW TRANSPLANT IN PRECLINICAL MODEL
Hematopoietic stem cell transplantation remains the only fully curative therapy for myelodysplastic syndromes (MDS). Tissue iron overload and non-transferrin bound iron (NTBI) have emerged as adverse prognostic factors for post-transplant survival of MDS patients.
Recently, we showed that preparatory chemotherapy conditioning in wild-type mice resulted in peri-transplant elevation of serum iron, transferrin (Tf) saturation and NTBI formation. Pre-conditioning TMPRSS6 silencing through a GalNAc-conjugated siRNA, by increasing hepcidin levels, prevented these changes in iron parameters. Here we asked whether these observations hold true in a pathologic condition which may require HSCT, such as MDS and how iron restriction impacts on bone marrow transplant outcome. To this aim, we administered pre-conditioning the GalNAc TMPRSS6 siRNA as iron restriction strategy to CD45.2+ MDS mice, which afterwards received chemotherapy and transplant of CD45.1+ wild-type BM cells.
Importantly, conditioning exacerbated the elevated systemic iron levels in MDS mice, which was prevented by pre-conditioning TMPRSS6 silencing. Iron-restricted MDS mice receiving BMT showed a superior blood chimerism, as indicated by higher circulating CD45.1+donor cells. This resulted from a superior multilineage engraftment of hematopoietic cells in the BM and spleen of iron-restricted recipient MDS mice compared to controls. Finally, donor chimerism of HSPCs was higher in iron-restricted versus control MDS mice undergoing transplant.
Overall, these data suggest that conditioning-elicited NTBI is a critical mediator of peri-transplant toxicity and adversely impacts transplant outcome. Peri-transplant application of novel iron restriction strategies aimed at reducing conditioning-elicited NTBI, by positively affecting transplant outcome, is of potential benefit for MDS patients undergoing BMT.
Recently, we showed that preparatory chemotherapy conditioning in wild-type mice resulted in peri-transplant elevation of serum iron, transferrin (Tf) saturation and NTBI formation. Pre-conditioning TMPRSS6 silencing through a GalNAc-conjugated siRNA, by increasing hepcidin levels, prevented these changes in iron parameters. Here we asked whether these observations hold true in a pathologic condition which may require HSCT, such as MDS and how iron restriction impacts on bone marrow transplant outcome. To this aim, we administered pre-conditioning the GalNAc TMPRSS6 siRNA as iron restriction strategy to CD45.2+ MDS mice, which afterwards received chemotherapy and transplant of CD45.1+ wild-type BM cells.
Importantly, conditioning exacerbated the elevated systemic iron levels in MDS mice, which was prevented by pre-conditioning TMPRSS6 silencing. Iron-restricted MDS mice receiving BMT showed a superior blood chimerism, as indicated by higher circulating CD45.1+donor cells. This resulted from a superior multilineage engraftment of hematopoietic cells in the BM and spleen of iron-restricted recipient MDS mice compared to controls. Finally, donor chimerism of HSPCs was higher in iron-restricted versus control MDS mice undergoing transplant.
Overall, these data suggest that conditioning-elicited NTBI is a critical mediator of peri-transplant toxicity and adversely impacts transplant outcome. Peri-transplant application of novel iron restriction strategies aimed at reducing conditioning-elicited NTBI, by positively affecting transplant outcome, is of potential benefit for MDS patients undergoing BMT.