Bone marrow failure syndromes and MDS represent a heterogenous group of diseases, characterized by ineffective myelopoiesis, the risk of clonal evolution and a generally poor response to chemotherapy-based treatment regimen. Nitrostyrene derivatives have been studied as protein phosphatase inhibitors in various tumor models. Pharmacological studies have identified nitrostyrene as the structural core underlying a pro-apoptotic effect in tumor cells, yet their effects on normal cells, including those of the hematopoietic system, are largely unknown. In this study, utilizing umbilical cord blood-derived myeloid progenitor cells, patient-derived bone marrow cells, and a (BALB/c) mouse model; we investigated the effects of treatment with two nitrostyrene derivatives (NTS1 and NTS2) on myeloid development. We demonstrate that these compounds stimulate the expansion and differentiation of myeloid progenitors in vitro and improve myeloid reconstitution after chemotherapy-induced bone marrow depletion in vitro and in vivo. These effects were accompanied by increased C/EBP? expression and activity and inhibition of the p38MAPK signalling pathway. Together, our data suggest that nitrostyrenes improve myelopoiesis and represent potential new treatment strategies for patients suffering from bone marrow failure syndromes, hypocellular myelodysplastic syndrome and chemotherapy-induced aplasia.
The clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis.
Valproic acid (VPA) has been used for decades in the treatment of epilepsy and psychiatric disorders, and the long-term use of VPA is regularly accompanied by hematological toxicity, including neutropenia. More recently, it has been demonstrated that VPA can be used as a histone deacetylase inhibitor (HDACi) for the treatment of hematological malignancies. In order to determine the specific effects of VPA in both hematological malignancies and normal hematopoiesis, recent studies have demonstrated that VPA treatment affects the differentiation of normal myeloid progenitors in vitro. In this study, we demonstrate that in a large patient population treated for neurological or psychiatric disorders, VPA treatment affects neutrophil as well as lymphocyte subset counts.
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