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MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model

Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis,...

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Autores principales: Pereira-Martins, Diego A., Weinhäuser, Isabel, Coelho-Silva, Juan Luiz, França-Neto, Pedro L., Almeida, Luciana Y., Bianco, Thiago M., Silva, Cleide L., França, Rafael F., Traina, Fabiola, Rego, Eduardo M., Schuringa, Jan Jacob, Lucena-Araujo, Antonio R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024355/
https://www.ncbi.nlm.nih.gov/pubmed/33824267
http://dx.doi.org/10.1038/s41419-021-03604-z
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author Pereira-Martins, Diego A.
Weinhäuser, Isabel
Coelho-Silva, Juan Luiz
França-Neto, Pedro L.
Almeida, Luciana Y.
Bianco, Thiago M.
Silva, Cleide L.
França, Rafael F.
Traina, Fabiola
Rego, Eduardo M.
Schuringa, Jan Jacob
Lucena-Araujo, Antonio R.
author_facet Pereira-Martins, Diego A.
Weinhäuser, Isabel
Coelho-Silva, Juan Luiz
França-Neto, Pedro L.
Almeida, Luciana Y.
Bianco, Thiago M.
Silva, Cleide L.
França, Rafael F.
Traina, Fabiola
Rego, Eduardo M.
Schuringa, Jan Jacob
Lucena-Araujo, Antonio R.
author_sort Pereira-Martins, Diego A.
collection PubMed
description Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5(high) transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5(low) blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation.
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spelling pubmed-80243552021-04-21 MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model Pereira-Martins, Diego A. Weinhäuser, Isabel Coelho-Silva, Juan Luiz França-Neto, Pedro L. Almeida, Luciana Y. Bianco, Thiago M. Silva, Cleide L. França, Rafael F. Traina, Fabiola Rego, Eduardo M. Schuringa, Jan Jacob Lucena-Araujo, Antonio R. Cell Death Dis Article Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5(high) transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5(low) blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation. Nature Publishing Group UK 2021-04-06 /pmc/articles/PMC8024355/ /pubmed/33824267 http://dx.doi.org/10.1038/s41419-021-03604-z Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pereira-Martins, Diego A.
Weinhäuser, Isabel
Coelho-Silva, Juan Luiz
França-Neto, Pedro L.
Almeida, Luciana Y.
Bianco, Thiago M.
Silva, Cleide L.
França, Rafael F.
Traina, Fabiola
Rego, Eduardo M.
Schuringa, Jan Jacob
Lucena-Araujo, Antonio R.
MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title_full MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title_fullStr MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title_full_unstemmed MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title_short MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
title_sort mll5 improves atra driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024355/
https://www.ncbi.nlm.nih.gov/pubmed/33824267
http://dx.doi.org/10.1038/s41419-021-03604-z
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