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

• Published in: Communications biology Vol. 6; no. 1; p. 295
• Main Authors: Taghi Khani, Adeleh, Kumar, Anil, Sanchez Ortiz, Ashly, Radecki, Kelly C., Aramburo, Soraya, Lee, Sung June, Hu, Zunsong, Damirchi, Behzad, Lorenson, Mary Y., Wu, Xiwei, Gu, Zhaohui, Stohl, William, Sanz, Ignacio, Meffre, Eric, Müschen, Markus, Forman, Stephen J., Koff, Jean L., Walker, Ameae M., Swaminathan, Srividya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 38/23; 631/67/1990/291/1621/1915; 64; 64/60; 692/420/755; 96; 96/1; 96/21; 96/31; 96/95; Activation-induced cytidine deaminase; Animal models; Animals; Apoptosis; Autocrine signalling; B-cell lymphoma; Biology; Biomedical and Life Sciences; Cell culture; Cell survival; Cell viability; Cytidine deaminase; Evolution; Humans; Immunoproliferative diseases; Isoforms; Life Sciences; Lupus Erythematosus, Systemic; Lymphocytes; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - genetics; Malignancy; Mice; Myc protein; Prolactin; Prolactin - genetics; Prolactin receptors; Protein Isoforms - genetics; Proto-Oncogene Proteins c-bcl-2; Receptors, Prolactin - genetics; Receptors, Prolactin - metabolism; Systemic lupus erythematosus; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04667-8

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. Malignant human B cells express autocrine prolactin (PRL), which has the potential to engage the long isoform and intermediate form of the PRL receptor to promote proliferation and/or survival.