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The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors
Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage le...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320370/ https://www.ncbi.nlm.nih.gov/pubmed/30610188 http://dx.doi.org/10.1038/s41467-018-07846-y |
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author | Nayak, R. C. Hegde, S. Althoff, M. J. Wellendorf, A. M. Mohmoud, F. Perentesis, J. Reina-Campos, M. Reynaud, D. Zheng, Y. Diaz-Meco, M. T. Moscat, J. Cancelas, J. A. |
author_facet | Nayak, R. C. Hegde, S. Althoff, M. J. Wellendorf, A. M. Mohmoud, F. Perentesis, J. Reina-Campos, M. Reynaud, D. Zheng, Y. Diaz-Meco, M. T. Moscat, J. Cancelas, J. A. |
author_sort | Nayak, R. C. |
collection | PubMed |
description | Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL(+) leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCζ behaves as a leukemic suppressor, aPKCλ/ι is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC λ/ι-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKCλ/ι-SATB2 signaling cascade is required for leukemic BCR-ABL(+) B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition. |
format | Online Article Text |
id | pubmed-6320370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63203702019-01-07 The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors Nayak, R. C. Hegde, S. Althoff, M. J. Wellendorf, A. M. Mohmoud, F. Perentesis, J. Reina-Campos, M. Reynaud, D. Zheng, Y. Diaz-Meco, M. T. Moscat, J. Cancelas, J. A. Nat Commun Article Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL(+) leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCζ behaves as a leukemic suppressor, aPKCλ/ι is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC λ/ι-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKCλ/ι-SATB2 signaling cascade is required for leukemic BCR-ABL(+) B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition. Nature Publishing Group UK 2019-01-04 /pmc/articles/PMC6320370/ /pubmed/30610188 http://dx.doi.org/10.1038/s41467-018-07846-y Text en © The Author(s) 2019 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 Nayak, R. C. Hegde, S. Althoff, M. J. Wellendorf, A. M. Mohmoud, F. Perentesis, J. Reina-Campos, M. Reynaud, D. Zheng, Y. Diaz-Meco, M. T. Moscat, J. Cancelas, J. A. The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title | The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title_full | The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title_fullStr | The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title_full_unstemmed | The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title_short | The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors |
title_sort | signaling axis atypical protein kinase c λ/ι-satb2 mediates leukemic transformation of b-cell progenitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320370/ https://www.ncbi.nlm.nih.gov/pubmed/30610188 http://dx.doi.org/10.1038/s41467-018-07846-y |
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