A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency
A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency
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DOI：
10.1016/j.cell.2007.05.014
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发表时间：
2007-06-15
期刊：
影响因子：
64.5
通讯作者：
Purton, Louise E.
中科院分区：
文献类型：
--
作者：
Walkley, Carl R.;Olsen, Gemma Haines;Purton, Louise E.
骨髓增生性综合征(IMPS)是一类异质性的非淋巴系造血肿瘤，被认为是造血细胞固有的。MPS的原因在很大程度上是未知的。在这里，我们证明了缺乏维甲酸受体伽马(RAR伽马)的小鼠，仅由RAR伽马缺乏的微环境诱导的MPS。RARγ(-/-)小鼠的骨髓(BM)、外周血和脾中粒细胞/巨噬细胞前体细胞和粒细胞显著增加。MPS表型在小鼠的寿命中持续存在，在老年小鼠中表现得更加明显。出乎意料的是，移植研究显示这种疾病并不是造血细胞固有的。来自野生型小鼠的骨髓被移植到具有RAR伽马(-/-)微环境的小鼠体内后迅速发展为MPS，部分原因是RAR伽马(-/-)小鼠体内显著升高的肿瘤坏死因子α。这些数据表明，RARγ的丢失导致了非造血细胞固有的MPS，揭示了微环境是造血疾病的唯一原因的能力。
Myeloproliferative syndromes (IMPS) are a heterogeneous subclass of nonlymphoid hematopoietic neoplasms which are considered to be intrinsic to hematopoietic cells. The causes of MPS are largely unknown. Here, we demonstrate that mice deficient for retinoic acid receptor gamma (RAR gamma), develop MPS induced solely by the RAR gamma-deficient microenvironment. RAR gamma(-/-) mice had significantly increased granulocyte/macrophage progenitors and granulocytes in bone marrow (BM), peripheral blood, and spleen. The MPS phenotype continued for the lifespan of the mice and was more pronounced in older mice. Unexpectedly, transplant studies revealed this disease was not intrinsic to the hematopoietic cells. BM from wild-type mice transplanted into mice with an RAR gamma(-/-) microenvironment rapidly developed the MPS, which was partially caused by significantly elevated TNF alpha in RAR gamma(-/-) mice. These data show that loss of RAR gamma results in a nonhematopoietic cell-intrinsic MPS, revealing the capability of the microenvironment to be the sole cause of hematopoietic disorders.