Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
Communications biology - 6(2023), 1 vom: 20. März, Seite 295 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Taghi Khani, Adeleh [VerfasserIn] |
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| Links: |
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| Themen: |
9002-62-4 |
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| Anmerkungen: |
Date Completed 22.03.2023 Date Revised 30.08.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42003-023-04667-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35446700X |
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| 100 | 1 | |a Taghi Khani, Adeleh |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 22.03.2023 | ||
| 500 | |a Date Revised 30.08.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Receptors, Prolactin |2 NLM | |
| 650 | 7 | |a Prolactin |2 NLM | |
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| 650 | 7 | |a Protein Isoforms |2 NLM | |
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| 700 | 1 | |a Kumar, Anil |e verfasserin |4 aut | |
| 700 | 1 | |a Sanchez Ortiz, Ashly |e verfasserin |4 aut | |
| 700 | 1 | |a Radecki, Kelly C |e verfasserin |4 aut | |
| 700 | 1 | |a Aramburo, Soraya |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Sung June |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Zunsong |e verfasserin |4 aut | |
| 700 | 1 | |a Damirchi, Behzad |e verfasserin |4 aut | |
| 700 | 1 | |a Lorenson, Mary Y |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Zhaohui |e verfasserin |4 aut | |
| 700 | 1 | |a Stohl, William |e verfasserin |4 aut | |
| 700 | 1 | |a Sanz, Ignacio |e verfasserin |4 aut | |
| 700 | 1 | |a Meffre, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Müschen, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Forman, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Koff, Jean L |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Ameae M |e verfasserin |4 aut | |
| 700 | 1 | |a Swaminathan, Srividya |e verfasserin |4 aut | |
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