Sex-BiasedZRSR2Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 06, 2021
- Source ID
- 10.1158/2159-8290.cd-20-1513
Entities
People
- Abner Louissaint Jr.
- Andrew A Lane
- Christopher A.G. Booth
- Christopher M. Kenyon
- David M Weinstock
- Elizabeth Morgan
- Fabrice Jardin
- Fanny Angelot-delettre
- Francine Garnache-ottou
- Gabriel K Griffin
- H. Phillip Koeffler
- Henry Yang
- Jia Li
- Justin Taylor
- Katsuhiro Togami
- Lucia Cabal-hierro
- Mahmoud Ghandi
- Marina Konopleva
- Michael Seiler
- Naveen Pemmaraju
- Omar Abdel-Wahab
- Peter S. Hammerman
- Pier Paolo Piccaluga
- Sabeha Biichle
- Scott B Lovitch
- Silvia Buonamici
- Sun Sook Chung
- Sunhee S. Kim
- Vikas Madan
- Yvonne Y. Li
Organizations
- American Society of Hematology
- Damon Runyon Cancer Research Foundation
- Doris Duke Charitable Foundation
- Harvard Medical School
- Harvard University
- Jomo Kenyatta University of Agriculture and Technology
- Massachusetts General Hospital
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- Sumitomo Foundation
- The Mark Foundation for Cancer Research
- UCLA David Geffen School of Medicine
- United States Department of Defense
- University of Miami
- University of Rouen-Normandy
- University of Texas at Austin