Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34+CD71+ precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14-dependent intrinsic (S100A8+) and extrinsic [tumour necrosis factor α (TNF-α)-overproduction] alterations of (CD169+) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71highTer119− immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro-erythroblasts. Marked Ery-Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p = 0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage-associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC-TD in MDS.del(5q).
Bibliographical noteFunding Information:
This work was supported by the German Cluster of Excellence program Regenerative Biology to Reconstructive Therapy, Humanized Mouse Models — Human Pathology (REBIRTH, project no. DFG‐24192914; Guntram Buesche), the US National Institutes of Health (NIH) (grant no. R01HL082945; Benjamin Ebert), a Gabrielle's Angel Award (Benjamin Ebert), a Leukaemia & Lymphoma Society Scholar and Specialized Center of Research (SCOR) award (Benjamin Ebert), the German Research Foundation (DFG1188/3‐1; Rebekka K. Schneider), a Max Eder fellowship provided by the German Cancer Aid (Deutsche Krebshilfe, grant no. 111750; Rebekka K. Schneider), and the Edward P. Evans Foundation (Rebekka K. Schneider).
© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.