Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Dyserythropoiesis
Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Dyserythropoiesis
ABSTRACT Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in elderly individuals. In this work, we analyzed the transcriptome of human HSCs purified from young and elderly healthy donors, as well as MDS patients, identifying transcriptional alterations following eight different patterns of expression. While aging-associated lesions seemed to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detected the upregulation of the transcription factor DDIT3. Overexpression of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis. Such effect was associated with downregulation of transcription factors required for normal erythropoiesis, and with a failure in the activation of their transcriptional programs. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia was able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing MDS patients. STATEMENT OF SIGNIFICANCEThis study defines how human aging and MDS development are characterized by transcriptional alterations in HSCs that follow different patterns, some of which may contribute to myeloid transformation. Among them, we demonstrate how MDS-specific upregulation of DDIT3 in HSCs induces dyserythropoiesis, while its knockdown in HSPCs from MDS patients restores proper erythroid differentiation.
Alfonso-Pierola Ana、Ezponda Teresa、Martin Patxi San、Ordo?ez Raquel、Alignani Diego、Castro Laura、San-Julian Mikel、Jimenez Tamara、L¨?pez F¨|lix、Montoro Julia、Huerga Sof¨aa、Copley Findlay、D¨aez-Campelo Mar¨aa、Serrano Guillermo、Rouault-Pierre Kevin、Valcarcel David、Philippe C¨|line、Maurano Matthew T.、Prosper Felipe、Muntion Sandra、Vilas Amaia、Taz¨?n B¨￠rbara、Berastegui Nerea、Molero Antonieta、Romero Juan P.、Diaz-Mazkiaran Aintzane、Hernaez Mikel、Lara-Astiaso David、Lamo-Espinosa Jos¨| M.、Rio-Machin Ana、Sanchez-Guijo Fermin、Sarvide Sarai、Ainciburu Marina
Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC||Cl¨anica Universidad de Navarra, Universidad de Navarra¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONCInstitute for Systems Genetics, NYU School of Medicine¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONCCl¨anica Universidad de Navarra, Universidad de NavarraHematology, Hospital Universitario de Salamanca-IBSALHematology, Hospital Universitario de Salamanca-IBSALDepartment of Hematology, University Hospital Vall d?ˉHebronCl¨anica Universidad de Navarra, Universidad de NavarraDepartment of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC||Hematology, Hospital Universitario de Salamanca-IBSALComputational Biology Program, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Hematology, University Hospital Vall d?ˉHebronDepartment of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonInstitute for Systems Genetics, NYU School of Medicine||Department of Pathology, NYU School of Medicine¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC||Cl¨anica Universidad de Navarra, Universidad de NavarraHematology, Hospital Universitario de Salamanca-IBSAL¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONCDepartment of Hematology, University Hospital Vall d?ˉHebron¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONCDepartment of Hematology, University Hospital Vall d?ˉHebron¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Computational Biology Program, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC||Computational Biology Program, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)Cl¨anica Universidad de Navarra, Universidad de NavarraDepartment of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC||Hematology, Hospital Universitario de Salamanca-IBSAL¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC¨￠rea de Hemato-Oncolog¨aa, CIMA Universidad de Navarra, Instituto de Investigaci¨?n Sanitaria de Navarra (IDISNA)||Centro de Investigaci¨?n Biom¨|dica en Red de C¨￠ncer, CIBERONC
基础医学肿瘤学分子生物学
Agingmyelodysplastic syndromesHSCstranscriptome profilingerythropoiesis
Alfonso-Pierola Ana,Ezponda Teresa,Martin Patxi San,Ordo?ez Raquel,Alignani Diego,Castro Laura,San-Julian Mikel,Jimenez Tamara,L¨?pez F¨|lix,Montoro Julia,Huerga Sof¨aa,Copley Findlay,D¨aez-Campelo Mar¨aa,Serrano Guillermo,Rouault-Pierre Kevin,Valcarcel David,Philippe C¨|line,Maurano Matthew T.,Prosper Felipe,Muntion Sandra,Vilas Amaia,Taz¨?n B¨￠rbara,Berastegui Nerea,Molero Antonieta,Romero Juan P.,Diaz-Mazkiaran Aintzane,Hernaez Mikel,Lara-Astiaso David,Lamo-Espinosa Jos¨| M.,Rio-Machin Ana,Sanchez-Guijo Fermin,Sarvide Sarai,Ainciburu Marina.Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Dyserythropoiesis[EB/OL].(2025-03-28)[2025-06-13].https://www.biorxiv.org/content/10.1101/2021.09.08.459384.点此复制
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