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

Judith Hounjet, Linde Van Aerschot, Kim De Keersmaecker, Marc Vooijs, Kim R Kampen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1506-1512
Number of pages7
JournalFebs Letters
Volume598
Issue number12
Early online date9 Apr 2024
DOIs
Publication statusPublished - Jun 2024

Keywords

  • DMT1
  • NOTCH
  • T-ALL
  • T-cell leukemia
  • differentiation
  • hemtapoiesis

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