The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia

Ashish Banerjee, Nicole Andrea Mifsud, Robert J Bird, Cecily J Forsyth, Jeffrey Szer, Constantine Tam, Sybil V Kellner, Andrew P Grigg, Penelope Motum, Mark Bentley, Stephen Opat, George Grigoriadis

Research output: Contribution to journalArticleResearchpeer-review

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)-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.
Original languageEnglish
Pages (from-to)576 - 582
Number of pages7
JournalBritish Journal of Haematology
Volume168
Issue number4
DOIs
Publication statusPublished - 2015

Cite this

Banerjee, Ashish ; Mifsud, Nicole Andrea ; Bird, Robert J ; Forsyth, Cecily J ; Szer, Jeffrey ; Tam, Constantine ; Kellner, Sybil V ; Grigg, Andrew P ; Motum, Penelope ; Bentley, Mark ; Opat, Stephen ; Grigoriadis, George. / The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia. In: British Journal of Haematology. 2015 ; Vol. 168, No. 4. pp. 576 - 582.
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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)-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.",
author = "Ashish Banerjee and Mifsud, {Nicole Andrea} and Bird, {Robert J} and Forsyth, {Cecily J} and Jeffrey Szer and Constantine Tam and Kellner, {Sybil V} and Grigg, {Andrew P} and Penelope Motum and Mark Bentley and Stephen Opat and George Grigoriadis",
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The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia. / Banerjee, Ashish; Mifsud, Nicole Andrea; Bird, Robert J; Forsyth, Cecily J; Szer, Jeffrey; Tam, Constantine; Kellner, Sybil V; Grigg, Andrew P; Motum, Penelope; Bentley, Mark; Opat, Stephen; Grigoriadis, George.

In: British Journal of Haematology, Vol. 168, No. 4, 2015, p. 576 - 582.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Banerjee, Ashish

AU - Mifsud, Nicole Andrea

AU - Bird, Robert J

AU - Forsyth, Cecily J

AU - Szer, Jeffrey

AU - Tam, Constantine

AU - Kellner, Sybil V

AU - Grigg, Andrew P

AU - Motum, Penelope

AU - Bentley, Mark

AU - Opat, Stephen

AU - Grigoriadis, George

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AB - 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.

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