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.

中文翻译：

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缺乏铁反应元件的 DMT1 亚型通过 NOTCH 通路激活调节正常和恶性造血

天然抗性相关巨噬细胞蛋白 2（NRAMP 2；也称为 DMT1，由SLC11A2）主要以其铁运输活动而闻名。最近，缺乏铁反应元件（nonIRE）的 DMT1 亚型与异常的 NOTCH 通路活性相关。在本报告中，我们研究了 DMT1 nonIRE 在正常和恶性造血中的功能。小鼠中 Dmt1 nonIRE 的敲除表明它在造血干细胞分化中具有非典型功能：它的敲除抑制了沿骨髓和淋巴谱系的发育，同时促进血小板的产生。 Dmt1 nonIRE 敲低诱导的这些对造血系统的表型影响与 Notch/Myc 通路活性的抑制有关。相反，我们的数据表明 DMT1 nonIRE 过表达在增强 T 细胞白血病同源盒蛋白 1 中的 NOTCH 通路活性方面具有非典型功能（TLX1)‐缺陷性白血病。这项工作为未来使用多重打击 T 细胞急性淋巴细胞白血病 (T-ALL) 模型进一步研究 DMT1 nonIRE 在 T-ALL 疾病发生和进展中的功能奠定了基础。