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| Status |
Public on Sep 28, 2024 |
| Title |
Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis [PDX] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA sequencing of 11 BPDCN PDX samples and 3 normal pDC samples, either untreated or treated with 1 µg/ml R848 for 24 hours
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| Contributor(s) |
Lane AA, Togami K |
| Citation missing |
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| Submission date |
Sep 27, 2024 |
| Last update date |
Sep 28, 2024 |
| Contact name |
Christopher Booth |
| Organization name |
Dana-Farber Cancer Institute
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| Street address |
450 Brookline Ave
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (28)
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| GSM8544766 |
pDC_2, Untreated |
| GSM8544767 |
pDC_3, R848 treated |
| GSM8544768 |
pDC_3, Untreated |
| GSM8544769 |
PDX_1, R848 treated |
| GSM8544770 |
PDX_1, Untreated |
| GSM8544771 |
PDX_2, R848 treated |
| GSM8544772 |
PDX_2, Untreated |
| GSM8544773 |
PDX_3, R848 treated |
| GSM8544774 |
PDX_3, Untreated |
| GSM8544775 |
PDX_4, R848 treated |
| GSM8544776 |
PDX_4, Untreated |
| GSM8544777 |
PDX_5, R848 treated |
| GSM8544778 |
PDX_5, Untreated |
| GSM8544779 |
PDX_6, R848 treated |
| GSM8544780 |
PDX_6, Untreated |
| GSM8544781 |
PDX_7, R848 treated |
| GSM8544782 |
PDX_7, Untreated |
| GSM8544783 |
PDX_8, R848 treated |
| GSM8544784 |
PDX_8, Untreated |
| GSM8544785 |
PDX_9, R848 treated |
| GSM8544786 |
PDX_9, Untreated |
| GSM8544787 |
PDX_10, R848 treated |
| GSM8544788 |
PDX_10, Untreated |
| GSM8544789 |
PDX_11, R848 treated |
| GSM8544790 |
PDX_11, Untreated |
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| This SubSeries is part of SuperSeries: |
| GSE185983 |
Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis |
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| Relations |
| BioProject |
PRJNA1166330 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE278318_Gene_Counts.csv.gz |
1019.1 Kb |
(ftp)(http) |
CSV |
| GSE278318_Gene_TPM.csv.gz |
3.9 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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