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Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms

Authors: 
Taghi Khani A, Kumar A, Sanchez Ortiz A, Radecki C, Aramburo S, Lee SJ, Hu Z, Damirchi B,Lorenson MY, Wu X, Gu Z, Stohl W, Sanz I, Meffre E, Müschen M, Forman SJ, Koff JL, Walker AM. Swaminathan S
Citation: 
Commun Biol. 2023;6:295. doi:10.1038/s42003-023-04667-8
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.
Epub: 
Not Epub
Organism or Cell Type: 
NOD-SCID IL2Rγ−/− (NSG) mice xenografted
Delivery Method: 
Alzet osmotic pump Vivo-Morpholino