|
| Status |
Public on Sep 23, 2021 |
| Title |
Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes: almost complete loss of erythroid specification were observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a pro-inflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.
|
| |
|
| Overall design |
Directional paired-end bulk RNAseq of CD34-Lin-CD71+GYPA+ erythroblasts FACS-isolated from human bone marrow from healthy controls (n=3) and patients with Diamond- Blackfan anemia (n=3 transfusion-dependent; n=1 transfusion independent and n=1 steroid-dependent)
|
| |
|
| Contributor(s) |
Iskander D, Karadimitris A |
| Citation(s) |
34516827 |
| |
| Submission date |
Aug 10, 2021 |
| Last update date |
Sep 23, 2021 |
| Contact name |
Deena Iskander |
| E-mail(s) |
d.iskander@imperial.ac.uk
|
| Organization name |
Imperial College
|
| Street address |
Du Cane Road
|
| City |
London |
| ZIP/Postal code |
W12 0NN |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (8)
|
|
| Relations |
| BioProject |
PRJNA757274 |
| SRA |
SRP333860 |
Less...
More...