RT Journal Article SR Electronic T1 Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.29.360503 DO 10.1101/2020.10.29.360503 A1 Katsuhiro Togami A1 Sun Sook Chung A1 Vikas Madan A1 Christopher M. Kenyon A1 Lucia Cabal-Hierro A1 Justin Taylor A1 Sunhee S. Kim A1 Gabriel K. Griffin A1 Mahmoud Ghandi A1 Jia Li A1 Yvonne Y. Li A1 Fanny Angelot-Delettre A1 Sabeha Biichle A1 Michael Seiler A1 Silvia Buonamici A1 Scott B. Lovitch A1 Abner Louissaint, Jr. A1 Elizabeth A. Morgan A1 Fabrice Jardin A1 Pier Paolo Piccaluga A1 David M. Weinstock A1 Peter S. Hammerman A1 Henry Yang A1 Marina Konopleva A1 Naveen Pemmaraju A1 Francine Garnache-Ottou A1 Omar Abdel-Wahab A1 H. Phillip Koeffler A1 Andrew A. Lane YR 2020 UL http://biorxiv.org/content/early/2020/10/29/2020.10.29.360503.abstract AB Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation.STATEMENT OF SIGNIFICANCE Sex bias in cancer is well recognized but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.Competing Interest StatementAAL has received research funding from AbbVie and Stemline Therapeutics and consulting fees from N-of-One and Qiagen. GKG has received research funding from Calico Life Sciences and consulting fees from Moderna Therapeutics. MS and SB were employees of H3 Biomedicine at the time of this study. MS is currently an employee of Remix Therapeutics (Cambridge, MA).