MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia.
MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia.
复制标题
作者：
造血系统容易出现与年龄相关的疾病，从功能血细胞缺陷到肿瘤状态的发展。此类肿瘤常伴有反复出现的细胞遗传学异常，其中20号染色体长臂(Del20q)的缺失在髓系恶性肿瘤中很常见。Del20q最小缺失区域包含9个基因，包括MYBL2，它编码一种与维持基因组完整性有关的关键蛋白。在这里，我们显示了表达一半正常水平的Mybl2(Mybl2+/Δ)的小鼠随着年龄的增长会发展成各种髓系疾病。这些疾病包括骨髓增生性肿瘤、骨髓发育不良(MDS)和髓系白血病，反映了与del20q相关的人类状况。此外，对MDS患者的基因表达谱分析显示，无论del20q状态如何，MYBL2的水平都降低了，并证明了MYBL2RNA的低水平与与DNA复制和检查点控制通路相关的基因子集的表达降低之间存在很强的相关性。与人类数据平行，我们发现这些通路在我们的Mybl2+/Δ小鼠身上也受到了干扰。因此，这种新的小鼠模型是研究血液系统恶性肿瘤在衰老过程中发生和发展的一个有价值的工具，并可能为治疗方法的临床前测试提供一个平台。
The haematopoietic system is prone to age-related disorders ranging from deficits in functional blood cells to the development of neoplastic states. Such neoplasms often involve recurrent cytogenetic abnormalities, among which a deletion in the long arm of chromosome 20 (del20q) is common in myeloid malignancies. The del20q minimum deleted region contains nine genes, including MYBL2, which encodes a key protein involved in the maintenance of genome integrity. Here, we show that mice expressing half the normal levels of Mybl2 (Mybl2+/Δ) develop a variety of myeloid disorders upon ageing. These include myeloproliferative neoplasms, myelodysplasia (MDS) and myeloid leukaemia, mirroring the human conditions associated with del20q. Moreover, analysis of gene expression profiles from patients with MDS demonstrated reduced levels of MYBL2, regardless of del20q status and demonstrated a strong correlation between low levels of MYBL2 RNA and reduced expression of a subset of genes related to DNA replication and checkpoint control pathways. Paralleling the human data, we found that these pathways are also disturbed in our Mybl2+/Δ mice. This novel mouse model, therefore, represents a valuable tool for studying the initiation and progression of haematological malignancies during ageing, and may provide a platform for preclinical testing of therapeutic approaches.