HMGA2 overexpression. Mus musculus

Overexpression of high mobility group AT-hook 2 (HMGA2) associated with truncations of its 3’ untranslated region (UTR) with let-7 micro RNA-complementary sequences have been identified in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we generated transgenic mice (∆Hmga2 mice) with a 3’UTR-trncated Hmga2 cDNA that overexpress Hmga2 mRNA and protein in hematopoietic organs. ∆Hmga2 mice showed proliferative hematopoiesis that mimicked a myeloproliferative neoplasm (MPN)-like phenotype with increased numbers of all lineages of peripheral blood cells, hypercellular bone marrow (BM), splenomegaly with extramedullary erythropoiesis, and erythropoietin-independent erythroid colony formation compared to wild-type mice. ∆Hmga2 BM-derived cells took over most of hematopoiesis in competitive repopulations during serial BM transplants. When we bred mice with circulating PNH cells (Piga- mice) with ∆Hmga2 mice, the lack of GPI-linked proteins did not add an additional clonal advantage to the ∆Hmga2+ cells. In summary, our results showed that the overexpression of a 3’UTR-truncated Hmga2 leads to a proliferative hematopoiesis with clonal advantage, which may explain clonal expansion in PNH or MPN at the level of HSC. Overall design: Eight independent preparations of RNA, which included each 2 samples of KLS cells and MEP cells from ∆Hmga2 mice and 2 each from WT mice. Each preparation was made from 4 or 6 mice.

现已在阵发性睡眠性血红蛋白尿症（PNH）患者中发现，高迁移率族AT钩蛋白2（HMGA2）的过表达与其3’非翻译区（UTR）截短并丢失let-7微RNA互补序列相关。本研究构建了携带3’UTR截短型Hmga2 cDNA的转基因小鼠（∆Hmga2小鼠），该模型可在造血器官中过表达Hmga2 mRNA与蛋白。与野生型小鼠相比，∆Hmga2小鼠表现出增殖性造血表型，模拟骨髓增殖性肿瘤（MPN）样特征：外周血各谱系细胞数量均升高、骨髓细胞密度增高（BM）、脾大伴髓外造血，且可形成红细胞生成素非依赖性红系集落。在系列骨髓移植的竞争性重建造血实验中，∆Hmga2小鼠的骨髓来源细胞可占据绝大多数造血功能。将携带循环PNH细胞的Piga-小鼠与∆Hmga2小鼠杂交后发现，糖基磷脂酰肌醇连接蛋白（GPI-linked proteins）的缺失并未为∆Hmga2+细胞带来额外的克隆优势。综上，本研究结果表明，3’UTR截短型Hmga2的过表达可引发具有克隆优势的增殖性造血，该机制或可解释PNH或MPN中造血干细胞（HSC）水平的克隆扩增现象。实验整体设计：共设置8份独立的RNA样本制备，其中∆Hmga2小鼠的KLS细胞、巨核细胞-红细胞祖细胞（MEP细胞）各2份样本，野生型（WT）小鼠同理各2份样本；每份样本制备取材自4或6只小鼠。