Sex-Biased ZRSR2 Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis

Author:

Togami Katsuhiro1ORCID,Chung Sun Sook1ORCID,Madan Vikas2ORCID,Booth Christopher A.G.1ORCID,Kenyon Christopher M.1ORCID,Cabal-Hierro Lucia1,Taylor Justin34ORCID,Kim Sunhee S.1ORCID,Griffin Gabriel K.56,Ghandi Mahmoud6ORCID,Li Jia2,Li Yvonne Y.1,Angelot-Delettre Fanny7,Biichle Sabeha7,Seiler Michael8,Buonamici Silvia8,Lovitch Scott B.5ORCID,Louissaint Abner9,Morgan Elizabeth A.5ORCID,Jardin Fabrice10ORCID,Piccaluga Pier Paolo111213ORCID,Weinstock David M.16ORCID,Hammerman Peter S.1,Yang Henry2,Konopleva Marina14,Pemmaraju Naveen14ORCID,Garnache-Ottou Francine7,Abdel-Wahab Omar3,Koeffler H. Phillip21516,Lane Andrew A.1617ORCID

Affiliation:

1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

2. 2Cancer Science Institute of Singapore, National University of Singapore, Singapore.

3. 3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

4. 4Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida.

5. 5Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

6. 6Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

7. 7Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.

8. 8H3 Biomedicine, Cambridge, Massachusetts.

9. 9Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

10. 10Inserm U1245, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.

11. 11Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy.

12. 12Department of Biomolecular Strategies, Genetics, Avant-Garde Therapies and Neurosciences (SBGN), Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.

13. 13School of Health, Department of Pathology, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya.

14. 14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

15. 15Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California.

16. 16Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore.

17. 17Ludwig Center at Harvard, Boston, Massachusetts.

Abstract

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. 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. This article is highlighted in the In This Issue feature, p. 275

Funder

National Cancer Institute

U.S. Department of Defense

Sumitomo Foundation

Damon Runyon Cancer Research Foundation

Mark Foundation For Cancer Research

Doris Duke Charitable Foundation

Bertarelli Rare Cancers Fund

Ludwig Center at Harvard

American Society of Hematology

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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