Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2
Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2
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DOI：
10.1182/blood-2014-03-562694
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发表时间：
2015-05-28
期刊：
影响因子：
20.3
通讯作者：
Honda, Hiroaki
中科院分区：
文献类型：
--
作者：
Ueda, Takeshi;Nagamachi, Akiko;Honda, Hiroaki
我们以前报道过，作为-7/7q-综合征的候选基因克隆的Samd 9 L的缺陷与组蛋白去甲基化酶：F-box和富含亮氨酸的重复蛋白10（Fbxl 10，也称为Jhdm 1b，Kdm 2b和Ndy 1）的表达增强协同加速白血病。为了进一步研究Fbxl 10在白血病发生中的作用，我们产生了在造血干细胞（HSC）中过表达Fbxl 10的转基因（Tg）小鼠。有趣的是，FbxlllO Tg小鼠发展为具有完全转移的髓样或B淋巴样白血病。来自Tg小鼠的HSC表现出加速的G 0/G1-到-S转变，正常的G 0到G1进入，导致多效性祖细胞扩增。Fbxl 10 Tg HSC显示神经元特异性基因家族成员2（Nsg 2）的表达增强，并且Nsg 2在原代骨髓细胞中的强制表达导致未成熟细胞的扩增。此外，参与线粒体氧化磷酸化的基因在Fbxl 10 Tg HSC中显著富集，同时细胞腺苷59-三磷酸水平增加。此外，染色质免疫沉淀测序分析表明，Fbxl 10直接结合到Nsg 2和氧化磷酸化基因的调控区。这些发现将Fbxl 10定义为真正的癌基因，其表达失调有助于涉及代谢增殖优势和Nsg 2介导的分化受损的白血病的发展。
We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation.