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Status |
Public on Sep 26, 2022 |
Title |
Germline ERCC6L2 mutations lead to impaired erythropoiesis and reshaping of the bone marrow niche |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Despite the inclusion of inherited myeloid malignancies as a separate entity in the WHO Classification, our understanding of the etiology of familial leukemia remains limited. ERCC6L2-deficiency is a rare, life-threatening inherited condition that gives rise to bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) resulting from germline mutations in DNA repair factor ERCC6L2. Here we employ a lentiviral shRNA approach to functionally characterize the impact of ERCC6L2 loss on hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). By combining cell culture assays and transcriptomic analysis of knockdown and ERCC6L2-mutated patient cells, we find that ERCC6L2-deficiency reduces HSPC clonogenic potential and delays erythropoiesis, while in MSCs it induces a significant lineage skewing, with increased osteogenesis and suppressed adipogenesis. Altogether, we demonstrate that ERCC6L2-deficiency impacts both hematopoietic and stromal compartments, and that our ex vivo model recapitulates patient phenotypes, providing a robust system to study germline mutations in hematological malignancies.
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Overall design |
30 Samples. 6 patient bone marrow and 24 Primary cells. 2 knockdown and corresponding scramble samples per media condition, except for Erythroid media where there are 4 samples each across two batches.
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Contributor(s) |
Armes H, Bewicke-Copley F, Rio-Machin A, Wozniak A, Di Bella D, Philippe C, Tummala H, Wang J, Ezponda T, Prosper F, Dokal I, Vulliamy T, Kilpivaara O, Wartiovaara-Kautto U, Fitzgibbon J, Rouault-Pierre K |
Citation(s) |
36156210 |
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Submission date |
Dec 09, 2021 |
Last update date |
Jan 03, 2023 |
Contact name |
Findlay Bewicke-Copley |
E-mail(s) |
f.copley@qmul.ac.uk
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Organization name |
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London
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Street address |
John Vane Science Centre, Barts Cancer Institute
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City |
London |
ZIP/Postal code |
EC1M 6BQ |
Country |
United Kingdom |
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Platforms (1) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (30)
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Relations |
BioProject |
PRJNA787532 |
SRA |
SRP349996 |
Supplementary file |
Size |
Download |
File type/resource |
GSE190542_RAW.tar |
5.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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