Deferasirox, an iron chelator, impacts myeloid differentiation by modulating NF-kB activity via mitochondrial ROS.

Autor: Jeffries NE; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Sadreyev D; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Trull EC; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Chetal K; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Yvanovich EE; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Mansour MK; Department of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA., Sadreyev RI; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Sykes DB; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2024 Nov; Vol. 205 (5), pp. 2000-2007. Date of Electronic Publication: 2024 Sep 26.
DOI: 10.1111/bjh.19782
Abstrakt: The iron chelator deferasirox (DFX) is effective in the treatment of iron overload. In certain patients with myelodysplastic syndrome, DFX can also provide a dramatic therapeutic benefit, improving red blood cell production and decreasing transfusion requirements. Nuclear Factor-kappa B (NF-kB) signalling has been implicated as a potential mechanism behind this phenomenon, with studies focusing on the effect of DFX on haematopoietic progenitors. Here, we examine the phenotypic and transcriptional effects of DFX throughout myeloid cell maturation in both murine and human model systems. The effect of DFX depends on the stage of differentiation, with effects on mitochondrial reactive oxygen species (ROS) production and NF-kB pathway regulation that vary between progenitors and neutrophils. DFX triggers a greater increase in mitochondrial ROS production in neutrophils and this phenomenon is mitigated when cells are cultured in hypoxic conditions. Single-cell transcriptomic profiling revealed that DFX decreases the expression of NF-kB and MYC (c-Myc) targets in progenitors and decreases the expression of PU.1 (SPI1) gene targets in neutrophils. Together, these data suggest a role of DFX in impairing terminal maturation of band neutrophils.
(© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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