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Title: | The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: Implications for myelodysplasia and aplastic anaemia. | Authors: | Bird R.;Tam C.;Kellner S.;Grigg A.;Motum P.;Bentley M.;Opat S. ;Grigoriadis G. ;Szer J.;Banerjee A.;Mifsud N.A.;Forsyth C. | Institution: | (Banerjee, Grigoriadis) Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia (Banerjee, Grigoriadis) Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia (Mifsud) Departments of Medicine and Allergy, Immunology and Respiratory Medicine, Monash University, Clayton, VIC, Australia (Bird) Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia (Bird) School of Medicine, Griffith University, Brisbane, QLD, Australia (Forsyth) Haematology, Jarrett Street Specialist Centre, North Gosford, NSW, Australia (Szer) Clinical Haematology, Royal Melbourne Hospital, Melbourne, VIC, Australia (Tam) Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia (Kellner) Haematology, Cotton Tree Specialist Centre, Cotton Tree, QLD, Australia (Grigg) Department of Clinical Haematology, Austin Hospital, Heidelberg, VIC, Australia (Motum) Haematology Department, Liverpool Hospital, Liverpool, NSW, Australia (Bentley) Haematology, Queensland Haematology and Oncology Group, Brisbane, QLD, Australia (Opat, Grigoriadis) Clinical Haematology, Monash Health, Clayton, VIC, Australia (Grigoriadis) Department of Haematology, Alfred Health, Melbourne, Australia | Issue Date: | 25-Feb-2015 | Copyright year: | 2015 | Publisher: | Blackwell Publishing Ltd (E-mail: customerservices@oxonblackwellpublishing.com) | Place of publication: | United Kingdom | Publication information: | British Journal of Haematology. 168 (4) (pp 576-582), 2015. Date of Publication: 01 Feb 2015. | Journal: | British Journal of Haematology | Abstract: | Summary: 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)-kappaB 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-kappaB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.Copyright © 2014 John Wiley & Sons Ltd. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1111/bjh.13151 | PubMed URL: | 25271366 [http://www.ncbi.nlm.nih.gov/pubmed/?term=25271366] | ISSN: | 0007-1048 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/40861 | Type: | Article | Subjects: | in vitro study intracellular signaling iron chelation male mouse *myelodysplastic syndrome/dt [Drug Therapy] *myelodysplastic syndrome/th [Therapy] myelodysplastic syndrome/dt [Drug Therapy] myeloid metaplasia/dt [Drug Therapy] myeloid metaplasia/th [Therapy] nonhuman peripheral blood mononuclear cell pure red cell anemia/dt [Drug Therapy] pure red cell anemia/th [Therapy] refractory anemia/dt [Drug Therapy] refractory anemia with ringed sideroblasts/dt [Drug Therapy] refractory anemia with ringed sideroblasts/th [Therapy] refractory cytopenia with multilineage dysplasia/dt [Drug Therapy] refractory cytopenia with multilineage dysplasia/th [Therapy] T lymphocyte activation *transcription initiation treatment duration treatment response *deferasirox/dt [Drug Therapy] *deferasirox/po [Oral Drug Administration] *deferasirox/pd [Pharmacology] *immunoglobulin enhancer binding protein/ec [Endogenous Compound] tumor necrosis factor/ec [Endogenous Compound] erythroid response hypoplastic myelodysplastic syndrome/th [Therapy] neutrophil response platelet response low risk population animal cell antiinflammatory activity *aplastic anemia/dt [Drug Therapy] *aplastic anemia/th [Therapy] aplastic anemia/dt [Drug Therapy] article blood transfusion bone marrow derived macrophage chelation therapy chronic lymphatic leukemia/dt [Drug Therapy] chronic lymphatic leukemia/th [Therapy] clinical article cohort analysis concentration response controlled study cytokine production cytokine release drug effect drug mechanism female gene expression regulation human human cell hypoplastic myelodysplastic syndrome/dt [Drug Therapy] cohort analysis concentration response controlled study cytokine production cytokine release drug effect drug mechanism female gene expression regulation human human cell hypoplastic myelodysplastic syndrome / drug therapy in vitro study intracellular signaling iron chelation low risk population male mouse *myelodysplastic syndrome / *drug therapy / *therapy myelodysplastic syndrome / drug therapy myeloid metaplasia / drug therapy / therapy nonhuman peripheral blood mononuclear cell pure red cell anemia / drug therapy / therapy antiinflammatory activity refractory anemia with ringed sideroblasts / drug therapy / therapy refractory cytopenia with multilineage dysplasia / drug therapy / therapy T lymphocyte activation *transcription initiation treatment duration treatment response animal cell refractory anemia / drug therapy *aplastic anemia / *drug therapy / *therapy aplastic anemia / drug therapy Article blood transfusion bone marrow derived macrophage chelation therapy chronic lymphatic leukemia / drug therapy / therapy clinical article |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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