Evolution of severe (transfusion‐dependent) anaemia in myelodysplastic syndromes with 5q deletion is characterized by a macrophage‐associated failure of the eythropoietic niche

Abstract

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 RPS14dependent 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| 115 BUESCHE et al.

Digital image analysis of erythroblastic islands in myelodysplastic syndromes

“…EBIs are complex and dynamic erythropoietic units that evolve around the delicate interaction between erythroid precursors and "nursing" macrophages. 2,13 It has long been hypothesized that the deregulation of EBI plays a key role in MDS pathogenesis, 2,14 and the morphologic alteration of EBI can serve as a diagnostic clue. However, due to the difficulties in reliably identifying and quantifying EBIs and their features, such hypotheses are not well-explored.…”

“…12 Macrophage-associated failure of the erythropoietic niche was recently reported as a key factor of transfusion-dependent anemia in MDS. 13 Moreover, the successful reproduction of EBI disruption is regarded as a key feature in evaluating in vitro MDS models. 14 However, despite a few studies with somewhat conflicting findings, 12,15 the qualitative and quantitative morphologic features of EBIs are not well characterized in MDS, and across MDS subtypes.…”

“…EBI disruption is frequently observed and is believed to be one of the early changes in MDS 12 . Macrophage‐associated failure of the erythropoietic niche was recently reported as a key factor of transfusion‐dependent anemia in MDS 13 . Moreover, the successful reproduction of EBI disruption is regarded as a key feature in evaluating in vitro MDS models 14 .…”

Two’s company but three’s a blast!

“…The precise roles of EBI macrophages in erythropoiesis are not fully understood, but include cross-talk between erythroblasts and macrophages, critical for erythroblast survival, and macrophage engulfment of extruded erythroid nuclei in terminal erythropoiesis. 2 EBI dysfunction is increasingly recognized as contributing to the pathogenesis of anemia in diseases such as thalassemia 3 and myelodysplastic syndromes, 4 Conversely, treatment of mice with erythropoietin (Epo) increases the erythroid to myeloid cell ratio in EMBI. Furthermore, Epo elevates the absolute number of EMBI by approximately fourfold.…”

“…HSCT in SCID, Wiskott-Aldrich syndrome, and similar diseases has an excellent outcome when performed at an earlier age, partly attributable to children having accumulated fewer infections and IEI-related complications. [2][3][4][5][6] By contrast, IEI in adolescents and adults represent an entirely different category of disease. Many adults lack a definitive molecular diagnosis, making it a challenge to predict the natural history of their disease.…”