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

Abstract Prolactin (PRL) is elevated in B-cell mediated lymphoproliferative diseases and promotes B-cell survival. However, whether PRL or PRL receptors drive the initiation, establishment, and sustenance of B-cell malignancies is unknown. We measured 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 LFPRLR plus intermediate isoforms (LF/IFPRLR) in vitro in malignant human B cells. To knockdown LF/IFPRLRs without suppressing expression of the counteractive short PRLR isoforms (SFPRLRs), we employed splice-modulating DNA oligomers. In SLE-prone mice, LFPRLR knockdown reduced numbers and proliferation of B-cell subsets and lowered the risk of B-cell transformation by downregulating expression of activation-induced cytidine deaminase. LFPRLR knockdown in lymphoma-prone mice reduced B-cell numbers and their expression of BCL2. In overt human B-cell malignancies, LF/IFPRLR knockdown reduced B-cell viability and their MYC and BCL2 expression. Unlike their normal counterparts which produced no autocrine PRL and expressed SFPRLRs, malignant human B cells expressed autocrine PRL and often no SFPRLRs. Isoform-specific knockdown of the LF/IFPRLR was not toxic to mice or to normal human immune cells, suggesting it is a safe approach to block the evolution of B-cell malignancies.