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IL-4 contributes to thrombocytopenia in AML
apoptotic rate of MkP in AML (Online Supplementary Figure S3F) was linked to a lack of maturation. Thus we assessed the polyploidization of MK in AML BM, and found that MK with high ploidy (≥32N) were reduced to a significantly greater extent than those with low ploidy (8-16N) (Figure 3A). As with their proportions in normal hematopoietic cells, the proportion of high-ploidy MK remained stable whereas the proportions of 8N and 16N MK progressively increased, especially the proportion of 8N ones (Figure 3B). MK in late-stage AML BM exhibited a clear left shift of ploidy distribution (Figure 3C). To gain
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further insight into the changes of MK function in AML, we isolated MK from AML and healthy control BM for microarray assay (Online Supplementary Figure S4A). The thrombopoietin-Mpl axis is a main regulator of throm- bopoiesis, including MK maturation and platelet produc- tion. Our microarray data showed that the levels of Mpl expression in the two groups were similar (Online Supplementary Figure S4B). Gene expression data (GSE112942) showed downregulation of platelet signa- ture genes and α-granule genes in MK from AML (Figure 3D), implying insufficient cytoplasmic maturation. In
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haematologica | 2019; 104(10)
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Figure 1. Dynamic changes of hematopoietic stem and progenitor cells with megakaryocyte potential in acute myeloid leukemia. (A) Left, refined model of native megakaryocytic differentiation from the canonical and non-canonical routes. Right, representative flow cytometric plots of hematopoietic stem and progenitor cell subpopulations involved in megakaryocytic differentiation. (B, C) Total numbers (B) and proportions (C) of LT-HSC, MPP2, PreMegE and MkP in normal hematopoietic cells in mice bone marrow at the indicated time points of AML. Data were normalized to the values in healthy controls and are presented as the percentage (B) or fold-increase (C) of controls. Four to five mice for each time point, three independent experiments. Error bars represent the standard error of mean. LT-HSC: long- term hematopoietic stem cells; LKS: Lin-/c-Kit+/Sca-1+; MPP: multipotent progenitor, PreMegE: pre-megakaryocytic-erythroid; MkP: megakaryocyte progenitor; MK: megakaryocyte; ST-HSC: short-term hematopoietic stem cells.