TY - JOUR
T1 - Sex-Biased ZRSR2 Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis
AU - Togami, Katsuhiro
AU - Chung, Sun Sook
AU - Madan, Vikas
AU - Booth, Christopher A.G.
AU - Kenyon, Christopher M.
AU - Cabal-Hierro, Lucia
AU - Taylor, Justin
AU - Kim, Sunhee S.
AU - Griffin, Gabriel K.
AU - Ghandi, Mahmoud
AU - Li, Jia
AU - Li, Yvonne Y.
AU - Angelot-Delettre, Fanny
AU - Biichle, Sabeha
AU - Seiler, Michael
AU - Buonamici, Silvia
AU - Lovitch, Scott B.
AU - Louissaint, Abner
AU - Morgan, Elizabeth A.
AU - Jardin, Fabrice
AU - Piccaluga, Pier Paolo
AU - Weinstock, David M.
AU - Hammerman, Peter S.
AU - Yang, Henry
AU - Konopleva, Marina
AU - Pemmaraju, Naveen
AU - Garnache-Ottou, Francine
AU - Abdel-Wahab, Omar
AU - Koeffler, H. Phillip
AU - Lane, Andrew A.
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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-offunction 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.
AB - 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-offunction 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.
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U2 - 10.1158/2159-8290.CD-20-1513
DO - 10.1158/2159-8290.CD-20-1513
M3 - Article
C2 - 34615655
AN - SCOPUS:85119625344
SN - 2159-8274
VL - 12
SP - 522
EP - 541
JO - Cancer discovery
JF - Cancer discovery
IS - 2
ER -