{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:22:39Z","timestamp":1793330559179,"version":"4.5.0"},"reference-count":75,"publisher":"American Association for Cancer Research (AACR)","issue":"2","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":128,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["R37 CA225191"],"award-info":[{"award-number":["R37 CA225191"]}]},{"name":"National Cancer Institute","award":["R35 CA231958"],"award-info":[{"award-number":["R35 CA231958"]}]},{"name":"U.S. Department of Defense","award":["CA190171"],"award-info":[{"award-number":["CA190171"]}]},{"DOI":"10.13039\/100008608","name":"Sumitomo Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008608","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001021","name":"Damon Runyon Cancer Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001021","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014599","name":"Mark Foundation For Cancer Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014599","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Bertarelli Rare Cancers Fund"},{"DOI":"10.13039\/100016394","name":"Ludwig Center at Harvard","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016394","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 275<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-20-1513","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T15:05:12Z","timestamp":1641827112000},"page":"522-541","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Sex-Biased\n                    <i>ZRSR2<\/i>\n                    Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis"],"prefix":"10.1158","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8422-0008","authenticated-orcid":false,"given":"Katsuhiro","family":"Togami","sequence":"first","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7340-3359","authenticated-orcid":false,"given":"Sun Sook","family":"Chung","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-624X","authenticated-orcid":false,"given":"Vikas","family":"Madan","sequence":"additional","affiliation":[{"name":"2Cancer Science Institute of Singapore, National University of Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-6637","authenticated-orcid":false,"given":"Christopher A.G.","family":"Booth","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2991-328X","authenticated-orcid":false,"given":"Christopher M.","family":"Kenyon","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Cabal-Hierro","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4407-6325","authenticated-orcid":false,"given":"Justin","family":"Taylor","sequence":"additional","affiliation":[{"name":"3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"4Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6477-5679","authenticated-orcid":false,"given":"Sunhee S.","family":"Kim","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel K.","family":"Griffin","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"6Broad Institute of Harvard and MIT, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-2265","authenticated-orcid":false,"given":"Mahmoud","family":"Ghandi","sequence":"additional","affiliation":[{"name":"6Broad Institute of Harvard and MIT, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"2Cancer Science Institute of Singapore, National University of Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne Y.","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Angelot-Delettre","sequence":"additional","affiliation":[{"name":"7Universit\u00e9 Bourgogne Franche-Comt\u00e9, INSERM, EFS BFC, UMR1098, Interactions H\u00f4te-Greffon-Tumeur\/Ing\u00e9nierie Cellulaire et G\u00e9nique, Besan\u00e7on, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabeha","family":"Biichle","sequence":"additional","affiliation":[{"name":"7Universit\u00e9 Bourgogne Franche-Comt\u00e9, INSERM, EFS BFC, UMR1098, Interactions H\u00f4te-Greffon-Tumeur\/Ing\u00e9nierie Cellulaire et G\u00e9nique, Besan\u00e7on, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Seiler","sequence":"additional","affiliation":[{"name":"8H3 Biomedicine, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Buonamici","sequence":"additional","affiliation":[{"name":"8H3 Biomedicine, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-0105","authenticated-orcid":false,"given":"Scott B.","family":"Lovitch","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Abner","family":"Louissaint","sequence":"additional","affiliation":[{"name":"9Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5880-9337","authenticated-orcid":false,"given":"Elizabeth A.","family":"Morgan","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6804-7943","authenticated-orcid":false,"given":"Fabrice","family":"Jardin","sequence":"additional","affiliation":[{"name":"10Inserm U1245, Centre Henri Becquerel, Universit\u00e9 de Rouen, IRIB, Rouen, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-0595","authenticated-orcid":false,"given":"Pier Paolo","family":"Piccaluga","sequence":"additional","affiliation":[{"name":"11Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy."},{"name":"12Department of Biomolecular Strategies, Genetics, Avant-Garde Therapies and Neurosciences (SBGN), Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy."},{"name":"13School of Health, Department of Pathology, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8724-3907","authenticated-orcid":false,"given":"David M.","family":"Weinstock","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."},{"name":"6Broad Institute of Harvard and MIT, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Hammerman","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Yang","sequence":"additional","affiliation":[{"name":"2Cancer Science Institute of Singapore, National University of Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Konopleva","sequence":"additional","affiliation":[{"name":"14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1670-6513","authenticated-orcid":false,"given":"Naveen","family":"Pemmaraju","sequence":"additional","affiliation":[{"name":"14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francine","family":"Garnache-Ottou","sequence":"additional","affiliation":[{"name":"7Universit\u00e9 Bourgogne Franche-Comt\u00e9, INSERM, EFS BFC, UMR1098, Interactions H\u00f4te-Greffon-Tumeur\/Ing\u00e9nierie Cellulaire et G\u00e9nique, Besan\u00e7on, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Abdel-Wahab","sequence":"additional","affiliation":[{"name":"3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Phillip","family":"Koeffler","sequence":"additional","affiliation":[{"name":"2Cancer Science Institute of Singapore, National University of Singapore, Singapore."},{"name":"15Cedars-Sinai Medical Center, Division of Hematology\/Oncology, UCLA School of Medicine, Los Angeles, California."},{"name":"16Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7380-0226","authenticated-orcid":false,"given":"Andrew A.","family":"Lane","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts."},{"name":"6Broad Institute of Harvard and MIT, Cambridge, Massachusetts."},{"name":"17Ludwig Center at Harvard, Boston, 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