Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.
Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.
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间充质细胞群体有助于调节干细胞和恶性细胞生长的微环境。骨线细胞参与了造血干细胞的生态位。在此，我们报道了在间充质成骨祖细胞中选择性地缺失miRNA加工内切酶Dicer1，导致明显的造血障碍。造血改变影响到多个谱系，概括了人类骨髓增生异常综合征(MDS)的关键特征，包括急性髓系白血病的发展。这些变化是微环境依赖性的，并由骨线中的特定细胞诱导。DICER1−/−骨祖细胞表达SBDS水平降低，该基因在人类骨髓衰竭和白血病易感性Shwachman-Bodian-Diamond综合征中发生突变。骨祖细胞中SBD的缺失主要表现为Dicer1的缺失。这些数据表明，骨线状细胞的分化阶段特异性扰动可以导致复杂的血液系统疾病，并表明单个细胞元素雌激素在组织动态平衡中发挥的核心作用。他们揭示，造血微环境的原发变化可以引发继发性肿瘤疾病。
Mesenchymal cell populations contribute to microenvironments regulating stem cells and the growth of malignant cells. Osteolineage cells participate in the hematopoietic stem cell niche. Here, we report that deletion of the miRNA processing endonuclease Dicer1 selectively in mesenchymal osteoprogenitors induces markedly disordered hematopoiesis. Hematopoietic changes affected multiple lineages recapitulating key features of human myelodysplastic syndrome (MDS) including the development of acute myelogenous leukemia. These changes were microenvironment dependent and induced by specific cells in the osteolineage. Dicer1−/− osteoprogenitors expressed reduced levels of Sbds, the gene mutated in the human bone marrow failure and leukemia predisposition Shwachman-Bodian-Diamond Syndrome. Deletion of Sbds in osteoprogenitors largely phenocopied Dicer1 deletion. These data demonstrate that differentiation stage-specific perturbations in osteolineage cells can induce complex hematological disorders and indicate the central role individual cellular elements of ‘estroma’ can play in tissue homeostasis. They reveal that primary changes in the hematopoietic microenvironment can initiate secondary neoplastic disease.
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