Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms
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DOI：
10.1038/nature13383
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发表时间：
2014-08-07
期刊：
影响因子：
64.8
通讯作者：
Mendez-Ferrer, Simon
中科院分区：
文献类型：
--
作者：
Arranz, Lorena;Sanchez-Aguilera, Abel;Mendez-Ferrer, Simon
骨髓增生性肿瘤（MPN）是由造血干细胞（HSC）区室突变引起的疾病。大多数 MPN 患者在 HSCs1-4 中存在常见的 Janus 激酶 2 (JAK2) 基因获得性突变，该突变使该激酶持续活跃，导致细胞增殖失控。骨髓微环境可能有助于这一常见事件的临床结果。我们之前表明，受交感神经纤维支配的骨髓巢蛋白（+）间充质干细胞（MSC）可调节正常的HSC5,6。在这里，我们证明废除这一调节回路对于 MPN 发病机制至关重要。 MPN 患者和 HSC 中表达人 JAK2(V617F) 突变的小鼠的骨髓中，支持雪旺细胞和巢蛋白 (+) MSC 的交感神经纤维持续减少。出乎意料的是，MSC的减少并不是由于分化，而是由突变HSC产生的白细胞介素1β引发的骨髓神经损伤和雪旺细胞死亡引起。反过来，体内巢蛋白（+）细胞的耗竭或CXCL12的产生增加了突变型HSC的数量并加速了MPN的进展。相反，使用神经保护药物或拟交感神经药物可阻止突变型 HSC 的扩增。使用 β(3)-肾上腺素能激动剂治疗可恢复巢蛋白 (+) MSCs5,6 的交感神经调节，从而防止这些细胞的损失，并通过间接减少白血病干细胞的数量来阻止 MPN 进展。我们的结果表明，突变型 HSC 驱动的生态位损伤对 MPN 中的疾病表现至关重要，并将形成生态位的 MSC 及其神经调节确定为有希望的治疗靶点。
Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs1-4 that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow nestin(+) mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs5,6. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin(+) MSCs are consistently reduced in the bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1 beta produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with beta(3)-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs5,6 prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukaemic stem cells. Our results demonstrate that mutant-HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.