Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany.
Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, 69117 Heidelberg, Germany.
Cells. 2020 Nov 9;9(11):2443. doi: 10.3390/cells9112443.
Acute myeloid leukaemia (AML) is a haematopoietic malignancy caused by a combination of genetic and epigenetic lesions. Activation of the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represents a key driver mutation in 25-30% of AML patients. FLT3 is a class III receptor tyrosine kinase, which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD results in an altered signalling quality, which causes cell transformation. Recent evidence indicates an effect of FLT3 ITD on bone homeostasis in addition to haematological aberrations. Using gene expression data repositories of FLT3 ITD-positive AML patients, we identified activated cytokine networks that affect the formation of the haematopoietic niche by controlling osteoclastogenesis and osteoblast functions. In addition, aberrant oncogenic FLT3 signalling of osteogenesis-specific cytokines affects survival of AML patients and may be used for prognosis. Thus, these data highlight the intimate crosstalk between leukaemic and osteogenic cells within the osteohaematopoietic niche.
急性髓系白血病（AML）是一种由遗传和表观遗传损伤共同引起的造血恶性肿瘤。在 25-30%的 AML 患者中，癌蛋白 FLT3 ITD（具有内部串联重复的 Fms 样酪氨酸激酶）的激活代表了一个关键的驱动突变。FLT3 是一种 III 类受体酪氨酸激酶，在淋巴谱系和髓系造血祖细胞的细胞存活、增殖和分化中发挥作用。突变型 FLT3 ITD 导致信号转导质量改变，从而导致细胞转化。最近的证据表明，FLT3 ITD 除了引起血液学异常外，还会对骨稳态产生影响。我们利用 FLT3 ITD 阳性 AML 患者的基因表达数据存储库，鉴定出激活的细胞因子网络，通过控制破骨细胞生成和成骨细胞功能来影响造血龛的形成。此外，成骨细胞特异性细胞因子异常的致癌性 FLT3 信号转导会影响 AML 患者的生存，并且可能用于预后。因此，这些数据强调了在骨造血龛中白血病细胞和成骨细胞之间的密切串扰。
