Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
| Autor: | Adeleh Taghi Khani, Anil Kumar, Ashly Sanchez Ortiz, Kelly C. Radecki, Soraya Aramburo, Sung June Lee, Zunsong Hu, Behzad Damirchi, Mary Y. Lorenson, Xiwei Wu, Zhaohui Gu, William Stohl, Ignacio Sanz, Eric Meffre, Markus Müschen, Stephen J. Forman, Jean L. Koff, Ameae M. Walker, Srividya Swaminathan |
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| Rok vydání: | 2023 |
| Předmět: |
Lymphoma
Lupus Erythematosus Systemic B-Cell Medicine (miscellaneous) Lupus Hematology General Biochemistry Genetics and Molecular Biology Prolactin Mice Rare Diseases Proto-Oncogene Proteins c-bcl-2 Receptors Animals Humans Protein Isoforms 2.1 Biological and endogenous factors Aetiology General Agricultural and Biological Sciences Cancer |
| Zdroj: | Communications biology, vol 6, iss 1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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