Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia
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 Diam...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Association for the Advancement of Science
2021
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| _version_ | 1797079552375128064 |
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| author | Iskander, D Wang, G Heuston, EF Christodoulidou, C Psaila, B Ponnusamy, K Ren, H Mokhtari, Z Robinson, M Chaidos, A Trivedi, P Trasanidis, N Katsarou, A Szydlo, R Palii, CG Zaidi, MH Al-Oqaily, Q Caputo, VS Roy, A Harrington, Y Karnik, L Naresh, K Mead, AJ Thongjuea, S Brand, M de la Fuente, J Bodine, DM Roberts, I Karadimitris, A |
| author_facet | Iskander, D Wang, G Heuston, EF Christodoulidou, C Psaila, B Ponnusamy, K Ren, H Mokhtari, Z Robinson, M Chaidos, A Trivedi, P Trasanidis, N Katsarou, A Szydlo, R Palii, CG Zaidi, MH Al-Oqaily, Q Caputo, VS Roy, A Harrington, Y Karnik, L Naresh, K Mead, AJ Thongjuea, S Brand, M de la Fuente, J Bodine, DM Roberts, I Karadimitris, A |
| author_sort | Iskander, D |
| collection | OXFORD |
| description | 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 was 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 proinflammatory 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. |
| first_indexed | 2024-03-07T00:47:34Z |
| format | Journal article |
| id | oxford-uuid:8537a5fd-eb59-46b0-80f7-b19bd5159ab7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:47:34Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:8537a5fd-eb59-46b0-80f7-b19bd5159ab72022-03-26T21:56:08ZSingle-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8537a5fd-eb59-46b0-80f7-b19bd5159ab7EnglishSymplectic ElementsAmerican Association for the Advancement of Science2021Iskander, DWang, GHeuston, EFChristodoulidou, CPsaila, BPonnusamy, KRen, HMokhtari, ZRobinson, MChaidos, ATrivedi, PTrasanidis, NKatsarou, ASzydlo, RPalii, CGZaidi, MHAl-Oqaily, QCaputo, VSRoy, AHarrington, YKarnik, LNaresh, KMead, AJThongjuea, SBrand, Mde la Fuente, JBodine, DMRoberts, IKaradimitris, ARibosome 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 was 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 proinflammatory 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. |
| spellingShingle | Iskander, D Wang, G Heuston, EF Christodoulidou, C Psaila, B Ponnusamy, K Ren, H Mokhtari, Z Robinson, M Chaidos, A Trivedi, P Trasanidis, N Katsarou, A Szydlo, R Palii, CG Zaidi, MH Al-Oqaily, Q Caputo, VS Roy, A Harrington, Y Karnik, L Naresh, K Mead, AJ Thongjuea, S Brand, M de la Fuente, J Bodine, DM Roberts, I Karadimitris, A Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title | Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title_full | Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title_fullStr | Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title_full_unstemmed | Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title_short | Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia |
| title_sort | single cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in diamond blackfan anemia |
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