Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia

Journal article

Iskander, D., Wang,G., Heuston, E.F., Christodoulidou, C., Psaila, B., Ponnusamy, K., Ren, H., Mokhtari, Z., Robinson, M., Chaidos, A., Trivedi, P., Trasanidis, N., Katsarou, A., Szydlo, R., NISC Comparative Sequencing Program, Palii, C.G., Ziadi, Z., Al-Oqaily, Q., Caputo Galarce, V., Roy, A., Harrington, Y., Karnik, L., Naresh, K., Mead,A.J., Thongjuea, S., Brand, M., de la Fuente, J., Bodine, D.M., Roberts,I. and Karadimitris, A. (2021). Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia. Science Translational Medicine. 13 (610). https://doi.org/10.1126/scitranslmed.abf0113
AuthorsIskander, D., Wang,G., Heuston, E.F., Christodoulidou, C., Psaila, B., Ponnusamy, K., Ren, H., Mokhtari, Z., Robinson, M., Chaidos, A., Trivedi, P., Trasanidis, N., Katsarou, A., Szydlo, R., NISC Comparative Sequencing Program, Palii, C.G., Ziadi, Z., Al-Oqaily, Q., Caputo Galarce, V., Roy, A., Harrington, Y., Karnik, L., Naresh, K., Mead,A.J., Thongjuea, S., Brand, M., de la Fuente, J., Bodine, D.M., Roberts,I. and Karadimitris, A.
Abstract

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.

KeywordsGeneral Medicine
Year2021
JournalScience Translational Medicine
Journal citation13 (610)
PublisherAmerican Association for the Advancement of Science (AAAS)
ISSN1946-6234
1946-6242
Digital Object Identifier (DOI)https://doi.org/10.1126/scitranslmed.abf0113
Publication dates
Online08 Sep 2021
Print08 Sep 2021
Publication process dates
Deposited20 Oct 2021
Accepted author manuscript
Additional information

This is
the author’s version of the work. It is posted here by permission of the AAAS for personal
use, not for redistribution. The definitive version was published in Science Translational Medicine on
08/09/2021, DOI: 10.1126/scitranslmed.abf0113.

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