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Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy

Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase i...

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Autores principales: Kannan, Sankaranarayan, Irwin, Mary E., Herbrich, Shelley M., Cheng, Tiewei, Patterson, LaNisha L., Aitken, Marisa J. L., Bhalla, Kapil, You, M. James, Konopleva, Marina, Zweidler-McKay, Patrick A., Chandra, Joya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027903/
https://www.ncbi.nlm.nih.gov/pubmed/35453402
http://dx.doi.org/10.3390/antiox11040717
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author Kannan, Sankaranarayan
Irwin, Mary E.
Herbrich, Shelley M.
Cheng, Tiewei
Patterson, LaNisha L.
Aitken, Marisa J. L.
Bhalla, Kapil
You, M. James
Konopleva, Marina
Zweidler-McKay, Patrick A.
Chandra, Joya
author_facet Kannan, Sankaranarayan
Irwin, Mary E.
Herbrich, Shelley M.
Cheng, Tiewei
Patterson, LaNisha L.
Aitken, Marisa J. L.
Bhalla, Kapil
You, M. James
Konopleva, Marina
Zweidler-McKay, Patrick A.
Chandra, Joya
author_sort Kannan, Sankaranarayan
collection PubMed
description Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2–related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated in AML resistance. Here, we demonstrate that HO-1 is elevated in FLT3-ITD-bearing cells compared to FLT3-wild type (WT). Transient knockdown or inhibitor-based suppression of HO-1 enhances vulnerability to the TKI, quizartinib, in both TKI-resistant and sensitive primary AML and cell line models. NRF2 suppression (genetically or pharmacologically using brusatol) results in decreased HO-1, suggesting that TKI-resistance is dependent on an active NRF2-driven pathway. In AML-patient derived xenograft (PDX) models, brusatol, in combination with daunorubicin, reduces leukemia burden and prolongs survival. Cumulatively, these data encourage further development of brusatol and NRF2 inhibition as components of combination therapy for refractory AML.
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spelling pubmed-90279032022-04-23 Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy Kannan, Sankaranarayan Irwin, Mary E. Herbrich, Shelley M. Cheng, Tiewei Patterson, LaNisha L. Aitken, Marisa J. L. Bhalla, Kapil You, M. James Konopleva, Marina Zweidler-McKay, Patrick A. Chandra, Joya Antioxidants (Basel) Article Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2–related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated in AML resistance. Here, we demonstrate that HO-1 is elevated in FLT3-ITD-bearing cells compared to FLT3-wild type (WT). Transient knockdown or inhibitor-based suppression of HO-1 enhances vulnerability to the TKI, quizartinib, in both TKI-resistant and sensitive primary AML and cell line models. NRF2 suppression (genetically or pharmacologically using brusatol) results in decreased HO-1, suggesting that TKI-resistance is dependent on an active NRF2-driven pathway. In AML-patient derived xenograft (PDX) models, brusatol, in combination with daunorubicin, reduces leukemia burden and prolongs survival. Cumulatively, these data encourage further development of brusatol and NRF2 inhibition as components of combination therapy for refractory AML. MDPI 2022-04-05 /pmc/articles/PMC9027903/ /pubmed/35453402 http://dx.doi.org/10.3390/antiox11040717 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kannan, Sankaranarayan
Irwin, Mary E.
Herbrich, Shelley M.
Cheng, Tiewei
Patterson, LaNisha L.
Aitken, Marisa J. L.
Bhalla, Kapil
You, M. James
Konopleva, Marina
Zweidler-McKay, Patrick A.
Chandra, Joya
Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title_full Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title_fullStr Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title_full_unstemmed Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title_short Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy
title_sort targeting the nrf2/ho-1 antioxidant pathway in flt3-itd-positive aml enhances therapy efficacy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027903/
https://www.ncbi.nlm.nih.gov/pubmed/35453402
http://dx.doi.org/10.3390/antiox11040717
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