title: The oral iron chelator deferasirox inhibits NF-κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia.
abstract: The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-κB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-κB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.
authors.affiliation: Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia; Centre for Inflammatory Diseases, Monash University, Clayton, Vic., Australia.
authors.forename: Ashish
authors.initials: A
authors.lastname: Banerjee
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mifsud
authors.forename: Robert
authors.initials: R
authors.lastname: Bird
authors.forename: Cecily
authors.initials: C
authors.lastname: Forsyth
authors.forename: Jeff
authors.initials: J
authors.lastname: Szer
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.forename: Sybil
authors.initials: S
authors.lastname: Kellner
authors.forename: Andrew
authors.initials: A
authors.lastname: Grigg
authors.forename: Penelope
authors.initials: P
authors.lastname: Motum
authors.forename: Mark
authors.initials: M
authors.lastname: Bentley
authors.forename: Stephen
authors.initials: S
authors.lastname: Opat
authors.forename: George
authors.initials: G
authors.lastname: Grigoriadis
mesh_terms: D000741:Anemia, Aplastic / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D062085:RNA, Long Noncoding; D014158:Transcription, Genetic / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D016328:NF-kappa B; D062085:RNA, Long Noncoding; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C077885:XIST non-coding RNA; D003676:Deferoxamine; D000077588:Deferasirox
keywords: aplastic anaemia; biochemistry; blood diseases; chelation; myeloid function and development