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Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
Prolactin (PRL) is elevated in B-cell-mediated lymphoproliferative diseases and promotes B-cell survival. Whether PRL or PRL receptors drive the evolution of B-cell malignancies is unknown. We measure changes in B cells after knocking down the pro-proliferative, anti-apoptotic long isoform of the PR...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027679/ https://www.ncbi.nlm.nih.gov/pubmed/36941341 http://dx.doi.org/10.1038/s42003-023-04667-8 |
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author | Taghi Khani, Adeleh Kumar, Anil Sanchez Ortiz, Ashly Radecki, Kelly C. Aramburo, Soraya Lee, Sung June Hu, Zunsong Damirchi, Behzad Lorenson, Mary Y. Wu, Xiwei Gu, Zhaohui Stohl, William Sanz, Ignacio Meffre, Eric Müschen, Markus Forman, Stephen J. Koff, Jean L. Walker, Ameae M. Swaminathan, Srividya |
author_facet | Taghi Khani, Adeleh Kumar, Anil Sanchez Ortiz, Ashly Radecki, Kelly C. Aramburo, Soraya Lee, Sung June Hu, Zunsong Damirchi, Behzad Lorenson, Mary Y. Wu, Xiwei Gu, Zhaohui Stohl, William Sanz, Ignacio Meffre, Eric Müschen, Markus Forman, Stephen J. Koff, Jean L. Walker, Ameae M. Swaminathan, Srividya |
author_sort | Taghi Khani, Adeleh |
collection | PubMed |
description | Prolactin (PRL) is elevated in B-cell-mediated lymphoproliferative diseases and promotes B-cell survival. Whether PRL or PRL receptors drive the evolution of B-cell malignancies is unknown. We measure changes in B cells after knocking down the pro-proliferative, anti-apoptotic long isoform of the PRL receptor (LFPRLR) in vivo in systemic lupus erythematosus (SLE)- and B-cell lymphoma-prone mouse models, and the long plus intermediate isoforms (LF/IFPRLR) in human B-cell malignancies. To knockdown LF/IFPRLRs without suppressing expression of the counteractive short PRLR isoforms (SFPRLRs), we employ splice-modulating DNA oligomers. In SLE-prone mice, LFPRLR knockdown reduces numbers and proliferation of pathogenic B-cell subsets and lowers the risk of B-cell transformation by downregulating expression of activation-induced cytidine deaminase. LFPRLR knockdown in lymphoma-prone mice reduces B-cell numbers and their expression of BCL2 and TCL1. In overt human B-cell malignancies, LF/IFPRLR knockdown reduces B-cell viability and their MYC and BCL2 expression. Unlike normal B cells, human B-cell malignancies secrete autocrine PRL and often express no SFPRLRs. Neutralization of secreted PRL reduces the viability of B-cell malignancies. Knockdown of LF/IFPRLR reduces the growth of human B-cell malignancies in vitro and in vivo. Thus, LF/IFPRLR knockdown is a highly specific approach to block the evolution of B-cell neoplasms. |
format | Online Article Text |
id | pubmed-10027679 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100276792023-03-22 Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms Taghi Khani, Adeleh Kumar, Anil Sanchez Ortiz, Ashly Radecki, Kelly C. Aramburo, Soraya Lee, Sung June Hu, Zunsong Damirchi, Behzad Lorenson, Mary Y. Wu, Xiwei Gu, Zhaohui Stohl, William Sanz, Ignacio Meffre, Eric Müschen, Markus Forman, Stephen J. Koff, Jean L. Walker, Ameae M. Swaminathan, Srividya Commun Biol Article Prolactin (PRL) is elevated in B-cell-mediated lymphoproliferative diseases and promotes B-cell survival. Whether PRL or PRL receptors drive the evolution of B-cell malignancies is unknown. We measure changes in B cells after knocking down the pro-proliferative, anti-apoptotic long isoform of the PRL receptor (LFPRLR) in vivo in systemic lupus erythematosus (SLE)- and B-cell lymphoma-prone mouse models, and the long plus intermediate isoforms (LF/IFPRLR) in human B-cell malignancies. To knockdown LF/IFPRLRs without suppressing expression of the counteractive short PRLR isoforms (SFPRLRs), we employ splice-modulating DNA oligomers. In SLE-prone mice, LFPRLR knockdown reduces numbers and proliferation of pathogenic B-cell subsets and lowers the risk of B-cell transformation by downregulating expression of activation-induced cytidine deaminase. LFPRLR knockdown in lymphoma-prone mice reduces B-cell numbers and their expression of BCL2 and TCL1. In overt human B-cell malignancies, LF/IFPRLR knockdown reduces B-cell viability and their MYC and BCL2 expression. Unlike normal B cells, human B-cell malignancies secrete autocrine PRL and often express no SFPRLRs. Neutralization of secreted PRL reduces the viability of B-cell malignancies. Knockdown of LF/IFPRLR reduces the growth of human B-cell malignancies in vitro and in vivo. Thus, LF/IFPRLR knockdown is a highly specific approach to block the evolution of B-cell neoplasms. Nature Publishing Group UK 2023-03-20 /pmc/articles/PMC10027679/ /pubmed/36941341 http://dx.doi.org/10.1038/s42003-023-04667-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Taghi Khani, Adeleh Kumar, Anil Sanchez Ortiz, Ashly Radecki, Kelly C. Aramburo, Soraya Lee, Sung June Hu, Zunsong Damirchi, Behzad Lorenson, Mary Y. Wu, Xiwei Gu, Zhaohui Stohl, William Sanz, Ignacio Meffre, Eric Müschen, Markus Forman, Stephen J. Koff, Jean L. Walker, Ameae M. Swaminathan, Srividya Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title | Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title_full | Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title_fullStr | Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title_full_unstemmed | Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title_short | Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
title_sort | isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of b-cell neoplasms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027679/ https://www.ncbi.nlm.nih.gov/pubmed/36941341 http://dx.doi.org/10.1038/s42003-023-04667-8 |
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