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Status |
Public on Mar 27, 2023 |
Title |
Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing Other
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Summary |
Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
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Overall design |
This GEO repository contains single-cell sequencing data on the bone marrow of six healthy donors, five BPDCN patients without overt bone marrow involvement, and six BPDCN patients with bone marrow involvement. Whole genome and whole exome sequencing data for this study can be found on dbGaP.
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Web link |
https://www.ncbi.nlm.nih.gov/pubmed/37286599
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Contributor(s) |
Griffin GK, Booth CA, Togami K, Chung SS, Ssozi D, Verga JA, Bouyssou JM, Lee YS, Shanmugam V, Hornick JL, LeBoeuf NR, Morgan EA, Bernstein BE, Hovestadt V, van Galen P, Lane AA |
Citation(s) |
37286599 |
Submission date |
Mar 20, 2023 |
Last update date |
Jun 26, 2023 |
Contact name |
Peter van Galen |
E-mail(s) |
petervangalen@gmail.com, pvangalen@bwh.harvard.edu
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Organization name |
Brigham and Women's Hospital / Broad Institute of MIT and Harvard
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Department |
Hematology
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Lab |
Van Galen Lab
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Street address |
4 Blackfan Circle
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City |
Boston |
State/province |
Massachusetts |
ZIP/Postal code |
02115 |
Country |
USA |
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Platforms (2) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (111)
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Relations |
BioProject |
PRJNA946651 |
Supplementary file |
Size |
Download |
File type/resource |
GSE227690_BM_counts.tsv.gz |
44.8 Mb |
(ftp)(http) |
TSV |
GSE227690_BM_metadata.tsv.gz |
1.1 Mb |
(ftp)(http) |
TSV |
GSE227690_BM_norm.tsv.gz |
91.6 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt10Dx_counts.tsv.gz |
15.8 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt10Dx_metadata.tsv.gz |
345.4 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt10Dx_norm.tsv.gz |
27.6 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt10Rel_counts.tsv.gz |
9.7 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt10Rel_metadata.tsv.gz |
196.6 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt10Rel_norm.tsv.gz |
21.3 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt12Dx_counts.tsv.gz |
8.4 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt12Dx_metadata.tsv.gz |
217.2 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt12Dx_norm.tsv.gz |
19.7 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt12Rel_counts.tsv.gz |
5.0 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt12Rel_metadata.tsv.gz |
161.0 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt12Rel_norm.tsv.gz |
12.5 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt14Dx_counts.tsv.gz |
9.0 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt14Dx_metadata.tsv.gz |
226.4 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt14Dx_norm.tsv.gz |
20.2 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt15Dx_counts.tsv.gz |
5.2 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt15Dx_metadata.tsv.gz |
70.6 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt15Dx_norm.tsv.gz |
4.5 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt16Dx_counts.tsv.gz |
4.1 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt16Dx_metadata.tsv.gz |
86.9 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt16Dx_norm.tsv.gz |
11.3 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt1Dx_counts.tsv.gz |
2.3 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt1Dx_metadata.tsv.gz |
81.0 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt1Dx_norm.tsv.gz |
5.5 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt1Rem_counts.tsv.gz |
12.9 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt1Rem_metadata.tsv.gz |
322.1 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt1Rem_norm.tsv.gz |
28.1 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt5Dx_counts.tsv.gz |
4.7 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt5Dx_metadata.tsv.gz |
133.5 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt5Dx_norm.tsv.gz |
11.1 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt9Dx_counts.tsv.gz |
6.7 Mb |
(ftp)(http) |
TSV |
GSE227690_Pt9Dx_metadata.tsv.gz |
132.1 Kb |
(ftp)(http) |
TSV |
GSE227690_Pt9Dx_norm.tsv.gz |
15.6 Mb |
(ftp)(http) |
TSV |
GSE227690_RAW.tar |
540.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |