| Autor: |
Annatina Schnegg-Kaufmann, Julie A. I. Thoms, Golam Sarower Bhuyan, Henry R. Hampton, Lachlin Vaughan, Kayleigh Rutherford, Purvi M. Kakadia, Emma M. V. Johansson, Tim Failes, Greg M. Arndt, Jason Koval, Robert Lindeman, Pauline Warburton, Alba Rodriguez-Meira, Adam J. Mead, Ashwin Unnikrishnan, Stefan K. Bohlander, Elli Papaemmanuil, Omid Faridani, Christopher J. Jolly, Fabio Zanini, John E. Pimanda |
| Rok vydání: |
2022 |
| Předmět: |
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| Popis: |
Progressively acquired somatic mutations in hematopoietic stem cells are central to pathogenesis in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). They can lead to proliferative advantages, impaired differentiation and progressive cytopenias. MDS or CMML patients with high-risk disease are treated with hypomethylating agents including 5-azacytidine (AZA). Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated hematopoietic stem and progenitor cells (HSPCs). However, the contribution of mutated HSPCs to steadystate hematopoiesis in MDS and CMML is unclear. To address this, we characterised the somatic mutations of individual stem, progenitor (common myeloid progenitor, granulocyte monocyte progenitor, megakaryocyte erythroid progenitor), and matched circulating (monocyte, neutrophil, naïve B cell) haematopoietic cells in treatment naïve and AZA-treated MDS and CMML via high-throughput single cell genotyping. The mutational burden was similar across multiple hematopoietic cell types, and even the most mutated stem and progenitor clones maintained their capacity to differentiate to mature myeloid and, in some cases, lymphoid cell types in vivo. Our data show that even highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment.Key points*Highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment.*The mutational burden in matched bone marrow and peripheral blood cells in MDS and CMML was similar throughout myelopoiesis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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