The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes.
Nerea BerasteguiMarina AinciburuJuan P RomeroPaula Garcia-OlloquiAna Alfonso-PierolaCéline PhilippeAmaia Vilas-ZornozaPatxi San Martin-UrizRaquel Ruiz-HernandezAnder AbarrategiRaquel OrdoñezDiego AlignaniSarai SarvideLaura Castro-LabradorJosé M Lamo-EspinosaMikel San-JuliánTamara JimenezFélix López-CadenasSandra MuntionFermin M Sanchez-GuijoAntonieta MoleroMaria Julia MontoroBárbara TazónGuillermo SerranoAintzane Diaz-MazkiaranMikel HernaezSofía HuergaFindlay Bewicke-CopleyAna Rio-MachinMatthew T MauranoMaria Diez CampeloDavid ValcarcelKevin Rouault-PierreDavid Lara-AstiasoTeresa EzpondaFelipe ProsperPublished in: Nature communications (2022)
Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34 + cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients.
Keyphrases
- transcription factor
- end stage renal disease
- dna damage
- gene expression
- ejection fraction
- chronic kidney disease
- endothelial cells
- newly diagnosed
- peritoneal dialysis
- hematopoietic stem cell
- poor prognosis
- prognostic factors
- cell proliferation
- dna binding
- dendritic cells
- oxidative stress
- risk factors
- immune response
- induced pluripotent stem cells
- signaling pathway
- patient reported
- binding protein
- heat stress