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Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma

Multiple myeloma (MM) is a refractory plasma cell tumor. In myeloma cells, the transcription factor IRF4, the master regulator of plasma cells, is aberrantly upregulated and plays an essential role in oncogenesis. IRF4 forms a positive feedback loop with MYC, leading to additional tumorigenic proper...

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Autores principales: Ikeda, Sho, Tagawa, Hiroyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486179/
https://www.ncbi.nlm.nih.gov/pubmed/34310776
http://dx.doi.org/10.1111/cas.15087
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author Ikeda, Sho
Tagawa, Hiroyuki
author_facet Ikeda, Sho
Tagawa, Hiroyuki
author_sort Ikeda, Sho
collection PubMed
description Multiple myeloma (MM) is a refractory plasma cell tumor. In myeloma cells, the transcription factor IRF4, the master regulator of plasma cells, is aberrantly upregulated and plays an essential role in oncogenesis. IRF4 forms a positive feedback loop with MYC, leading to additional tumorigenic properties. In recent years, molecular targeted therapies have contributed to a significant improvement in the prognosis of MM. Nevertheless, almost all patients experience disease progression, which is thought to be a result of treatment resistance induced by various elements of the bone marrow microenvironment. Among these, the hypoxic response, one of the key processes for cellular homeostasis, induces hypoxia‐adapted traits such as undifferentiation, altered metabolism, and dissemination, leading to drug resistance. These inductions are caused by ectopic gene expression changes mediated by the activation of hypoxia‐inducible factors (HIFs). By contrast, the expression levels of IRF4 and MYC are markedly reduced by hypoxic stress. Notably, an anti‐apoptotic capability is usually acquired under both normoxic and hypoxic conditions, but the mechanism is distinct. This fact strongly suggests that myeloma cells may survive by switching their dependent regulatory factors from IRF4 and MYC (normoxic bone marrow region) to HIF (hypoxic bone marrow microenvironment). Therefore, to achieve deep remission, combination therapeutic agents, which are complementarily effective against both IRF4‐MYC‐dominant and HIF‐dominated fractions, may become an important therapeutic strategy for MM.
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spelling pubmed-84861792021-10-07 Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma Ikeda, Sho Tagawa, Hiroyuki Cancer Sci Review Articles Multiple myeloma (MM) is a refractory plasma cell tumor. In myeloma cells, the transcription factor IRF4, the master regulator of plasma cells, is aberrantly upregulated and plays an essential role in oncogenesis. IRF4 forms a positive feedback loop with MYC, leading to additional tumorigenic properties. In recent years, molecular targeted therapies have contributed to a significant improvement in the prognosis of MM. Nevertheless, almost all patients experience disease progression, which is thought to be a result of treatment resistance induced by various elements of the bone marrow microenvironment. Among these, the hypoxic response, one of the key processes for cellular homeostasis, induces hypoxia‐adapted traits such as undifferentiation, altered metabolism, and dissemination, leading to drug resistance. These inductions are caused by ectopic gene expression changes mediated by the activation of hypoxia‐inducible factors (HIFs). By contrast, the expression levels of IRF4 and MYC are markedly reduced by hypoxic stress. Notably, an anti‐apoptotic capability is usually acquired under both normoxic and hypoxic conditions, but the mechanism is distinct. This fact strongly suggests that myeloma cells may survive by switching their dependent regulatory factors from IRF4 and MYC (normoxic bone marrow region) to HIF (hypoxic bone marrow microenvironment). Therefore, to achieve deep remission, combination therapeutic agents, which are complementarily effective against both IRF4‐MYC‐dominant and HIF‐dominated fractions, may become an important therapeutic strategy for MM. John Wiley and Sons Inc. 2021-08-09 2021-10 /pmc/articles/PMC8486179/ /pubmed/34310776 http://dx.doi.org/10.1111/cas.15087 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Review Articles
Ikeda, Sho
Tagawa, Hiroyuki
Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title_full Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title_fullStr Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title_full_unstemmed Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title_short Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
title_sort impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486179/
https://www.ncbi.nlm.nih.gov/pubmed/34310776
http://dx.doi.org/10.1111/cas.15087
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