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Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
- Source :
- Communications biology, vol 6, iss 1
- Publication Year :
- 2023
- Publisher :
- eScholarship, University of California, 2023.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Communications biology, vol 6, iss 1
- Accession number :
- edsair.doi.dedup.....1a202e7efae31ab6bb332699274bb680