The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes

Autor: Nerea Berastegui, Marina Ainciburu, Juan P. Romero, Paula Garcia-Olloqui, Ana Alfonso-Pierola, Céline Philippe, Amaia Vilas-Zornoza, Patxi San Martin-Uriz, Raquel Ruiz-Hernández, Ander Abarrategi, Raquel Ordoñez, Diego Alignani, Sarai Sarvide, Laura Castro-Labrador, José M. Lamo-Espinosa, Mikel San-Julian, Tamara Jimenez, Félix López-Cadenas, Sandra Muntion, Fermin Sanchez-Guijo, Antonieta Molero, Maria Julia Montoro, Bárbara Tazón, Guillermo Serrano, Aintzane Diaz-Mazkiaran, Mikel Hernaez, Sofía Huerga, Findlay Bewicke-Copley, Ana Rio-Machin, Matthew T. Maurano, María Díez-Campelo, David Valcarcel, Kevin Rouault-Pierre, David Lara-Astiaso, Teresa Ezponda, Felipe Prosper
Přispěvatelé: Institut Català de la Salut, [Berastegui N, Ainciburu M, Romero JP, Garcia-Olloqui P] Department of Hematology-Oncology, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. [Alfonso-Pierola A] Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. Department of Hematology, Clínica Universidad de Navarra, Universidad de Navarra and CCUN, Pamplona, Spain. [Philippe C] Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, England, UK. [Molero A, Montoro MJ, Tazón B, Valcarcel D] Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
Rok vydání: 2022
Předmět:
células::células de la médula ósea::células madre hematopoyéticas [ANATOMÍA]
Adult
Cells::Bone Marrow Cells::Hematopoietic Stem Cells [ANATOMY]
Multidisciplinary
Cèl·lules mare hematopoètiques
Hemic and Lymphatic Diseases::Hematologic Diseases::Bone Marrow Diseases::Myelodysplastic Syndromes [DISEASES]
General Physics and Astronomy
General Chemistry
Hematopoietic Stem Cells
General Biochemistry
Genetics and Molecular Biology
Gene Expression Regulation
Factors de transcripció
Myelodysplastic Syndromes
Humans
Erythropoiesis
enfermedades hematológicas y linfáticas::enfermedades hematológicas::enfermedades de la médula ósea::síndromes mielodisplásicos [ENFERMEDADES]
Transcription Factor CHOP
Síndromes mielodisplàsiques
Amino Acids
Peptides
and Proteins::Proteins::Transcription Factors [CHEMICALS AND DRUGS]
aminoácidos
péptidos y proteínas::proteínas::factores de transcripción [COMPUESTOS QUÍMICOS Y DROGAS]
Aged
Transcription Factors
Zdroj: Scientia
ISSN: 2041-1723
DOI: 10.1038/s41467-022-35192-7
Popis: Haematopoietic stem cells; Myelodysplastic syndrome; Transcriptomics Cèl·lules mare hematopoètiques; Síndrome mielodisplàstic; Transcriptòmica Células madre hematopoyéticas; Síndrome mielodisplásico; Transcriptómica 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. This work was supported by the Instituto de Salud Carlos III and co-financed by ERDF A way of making Europe (PI17/00701, and PI20/01308) (F.P.) and (PI19/00726) (T.E.), CIBERONC (CB16/12/00489) (F.P.); Gobierno de Navarra (AGATA 0011-1411-2020-000010/0011-1411-2020-000011 and DIANA 0011-1411-2017-000028/0011-1411-2017-000029/0011-1411-2017-000030) (F.P.); Fundación La Caixa (GR-NET NORMAL-HIT HR20-00871) (F.P.); and Cancer Research UK [C355/A26819], FC AECC and AIRC under the Accelerator Award Program, and MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe [RTI2018-101708-A-I00] (M.H.). Moreover, this work was supported by PhD fellowships from Gobierno de Navarra (0011-0537-2019-000001) (N.B.), and (0011-0537-2020-000022) (A.D.-M.); a PhD fellowship from Ministerio de Ciencia, Innovación y Universidades (FPU18/05488) (M.A.); an Investigador AECC award from the Fundación AECC (INVES19059EZPO) (T.E.), H2020 Marie S. Curie IF Action, European Commission, Grant Agreement No. 898356 (M.H.); and by grants RYC2018-025502-I (A.A.) and PRE2018-084542 (R.R.) funded by MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future. We particularly acknowledge the patients and healthy donors for their participation in this study, and the Biobank of the University of Navarra for its collaboration.
Databáze: OpenAIRE
Externí odkaz: