Abstract：
Natural resistance-associated macrophage protein 2 (NRAMP 2; also known as DMT1 and encoded by SLC11A2) is mainly known for its iron transport activity. Recently, the DMT1 isoform lacking the iron-response element (nonIRE) was associated with aberrant NOTCH pathway activity. In this report, we investigated the function of DMT1 nonIRE in normal and malignant hematopoiesis. Knockdown of Dmt1 nonIRE in mice showed that it has non-canonical functions in hematopoietic stem cell differentiation: its knockdown suppressed development along the myeloid and lymphoid lineages, while promoting the production of platelets. These phenotypic effects on the hematopoietic system induced by Dmt1 nonIRE knockdown were linked to suppression of Notch/Myc pathway activity. Conversely, our data indicate a non-canonical function for DMT1 nonIRE overexpression in boosting NOTCH pathway activity in T-cell leukemia homeobox protein 1 (TLX1)-defective leukemia. This work sets the stage for future investigation using a multiple-hit T-cell acute lymphoblastic leukemia (T-ALL) model to further investigate the function of DMT1 nonIRE in T-ALL disease development and progression.
摘要：
天然抗性相关巨噬细胞蛋白2（NRAMP2；也称为DMT1，由SLC11A2编码）主要以其铁转运活性而闻名。最近,缺乏铁反应元素(nonIRE)的DMT1亚型与异常的NOTCH途径活性相关.在这份报告中,我们研究了DMT1nonIRE在正常和恶性造血中的功能。小鼠中Dmt1nonIRE的敲低表明它在造血干细胞分化中具有非规范功能：其敲低抑制了沿髓系和淋巴系的发育，同时促进血小板的产生。Dmt1非IRE敲低诱导的造血系统的这些表型效应与Notch/Myc途径活性的抑制有关。相反，我们的数据表明DMT1nonIRE过表达在T细胞白血病同源盒蛋白1(TLX1)缺陷型白血病中增强NOTCH通路活性方面具有非典型功能.这项工作为使用多次击中T细胞急性淋巴细胞白血病（T-ALL）模型进一步研究DMT1nonIRE在T-ALL疾病发展和进展中的功能奠定了基础。
