The DMT1 isoform lacking the iron‐response element regulates normal and malignant hematopoiesis via NOTCH pathway activation

• Published in: FEBS letters Vol. 598; no. 12; pp. 1506 - 1512
• Main Authors: Hounjet, Judith, Van Aerschot, Linde, De Keersmaecker, Kim, Vooijs, Marc, Kampen, Kim R.
• Format: Journal Article
• Language: English
• Published: England 01-06-2024
• Subjects: Animals; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Differentiation; differentiation; DMT1; Hematopoiesis - genetics; Hematopoietic Stem Cells - metabolism; hemtapoiesis; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Iron - metabolism; Mice; NOTCH; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction; T‐ALL; T‐cell leukemia; NOTCH; differentiation; T‐cell leukemia; DMT1; T‐ALL; hemtapoiesis
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14870

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.
The authors find that, in normal hematopoiesis, the DMT1/SLC11A2 nonIRE isoform controls the hematopoietic stem cell pool by dictating differentiation of the myeloid and B cell lymphoid lineages while suppressing the production of platelets via Notch/Myc pathway regulation. In TLX1‐defective leukemia, DMT1 nonIRE boosts NOTCH pathway activity, known to be responsible for unlimited proliferation of leukemic cells.