nature

当前位置: Nature » 基因&基因组学 » 正文

急性髓性白血病的一个发病机制

摘要 : 由美国哥伦比亚大学等处的研究人员在一个小鼠模型中发现,激发成骨细胞中的及-catenin发生突变,足以引发“急性髓性白血病”(AML)的发病。相关文章发表于2014年1月15日的《Nature》杂志上。

 由美国哥伦比亚大学等处的研究人员在一个小鼠模型中发现,激发成骨细胞中的及-catenin发生突变,足以引发“急性髓性白血病”(AML)的发病。相关文章发表于2014年1月15日的《Nature》杂志上。

Nature:急性髓性白血病的一个发病机制

急性髓性白血病的一个发病机制

成骨细胞系会影响长期再植造血干细胞的数量和归巢,造血干细胞动员,血统的决定和B细胞淋巴细胞增殖。最近的一项小鼠研究中,成骨细胞被发现与白血病前期有关联。然而,并没有证据表明,成骨细胞可诱导白血病单个基因突变。

肿瘤微环境对肿瘤发生有深远影响,而基质细胞的基因改变会帮助癌症形成。

Stavroula Kousteni及同事在一个小鼠模型中发现,激发成骨细胞中的及-catenin发生突变,足以引发“急性髓性白血病”(AML)的发病。这些突变触发会激活造血细胞中的Notch信号通道的配体从成骨细胞中释放;Notch通道的抑制会改善病情。

关于在骨髓增生病患者和AML患者中患-catenin信号作用增强的发现表明,一个类似的机制可能会促使人患白血病。这些结果表明,成骨细胞可以诱导急性髓性白血病遗传改变,找出导致这种转变的分子信号,并提供一个急性髓细胞性白血病潜在的新的药物治疗方法。

原文摘要:

Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts

Aruna Kode, John S. Manavalan, Ioanna Mosialou, Govind Bhagat, Chozha V. Rathinam,Na Luo, Hossein Khiabanian, Albert Lee, Vundavalli V. Murty, Richard Friedman, Andrea Brum, David Park, Naomi Galili, Siddhartha Mukherjee, Julie Teruya-Feldstein, Azra Raza,Raul Rabadan, Ellin Berman & Stavroula Kousteni

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expressi0n of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

来源: 生物帮 浏览次数:32

热门文章TOP

RSS订阅 - 填写您的邮件地址,订阅我们的精彩内容: - 网站地图
网站联系电话:020-87540820 备案号:粤ICP备11050685号-8 增值电信业务经营许可证:粤B2-20120479
©2011-2015 生物帮 All rights reserved.