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

被引：9

作者：

Berastegui, Nerea ^{[1
,2
]}

Ainciburu, Marina ^{[1
,2
]}

Romero, Juan P. ^{[1
,2
]}

Garcia-Olloqui, Paula ^{[1
,2
]}

Alfonso-Pierola, Ana ^{[2
,3
,4
]}

Philippe, Celine ^{[5
]}

Vilas-Zornoza, Amaia ^{[1
,2
]}

San Martin-Uriz, Patxi ^{[1
]}

Ruiz-Hernandez, Raquel ^{[6
]}

Abarrategi, Ander ^{[6
,7
]}

Ordonez, Raquel ^{[8
]}

Alignani, Diego ^{[1
,2
]}

Sarvide, Sarai ^{[1
,2
]}

Castro-Labrador, Laura ^{[1
,2
]}

Lamo-Espinosa, Jose M. ^{[4
,9
]}

San-Julian, Mikel ^{[4
,9
]}

Jimenez, Tamara ^{[10
]}

Lopez-Cadenas, Felix ^{[10
]}

Muntion, Sandra ^{[10
]}

Sanchez-Guijo, Fermin ^{[2
,10
]}

Molero, Antonieta ^{[11
]}

Montoro, Maria Julia ^{[11
]}

Tazon, Barbara ^{[11
]}

Serrano, Guillermo ^{[12
]}

Diaz-Mazkiaran, Aintzane ^{[1
,12
]}

Hernaez, Mikel ^{[2
,12
]}

Huerga, Sofia ^{[3
,4
]}

Bewicke-Copley, Findlay ^{[13
]}

Rio-Machin, Ana ^{[13
]}

Maurano, Matthew T. ^{[8
,14
]}

Diez-Campelo, Maria ^{[2
,10
]}

Valcarcel, David ^{[11
]}

Rouault-Pierre, Kevin ^{[5
]}

Lara-Astiaso, David ^{[1
]}

Ezponda, Teresa ^{[1
,2
]}

Prosper, Felipe ^{[1
,2
,3
,4
]}

机构：

[1] CIMA Univ Navarra, Inst Invest Sanitaria Navarra IDISNA, Dept Hematol Oncol, Pamplona, Spain

[2] Inst Salud Carlos III, Ctr Invest Biomed Red Canc, CIBERONC, Madrid, Spain

[3] Univ Navarra, Clin Univ Navarra, Dept Hematol, Pamplona 31008, Spain

[4] CCUN, Pamplona 31008, Spain

[5] Queen Mary Univ London, Barts Canc Inst, Dept Haematooncol, London, England

[6] Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biomat CIC BiomaGUNE, San Sebastian, Spain

[7] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[8] NYU, Sch Med, Inst Syst Genet, New York, NY USA

[9] Univ Navarra, Clin Univ Navarra, Dept Orthoped Surg & Traumatol, Pamplona 31008, Spain

[10] Univ Salamanca, Hosp Univ Salamanca IBSAL, Dept Hematol, Salamanca, Spain

[11] Hosp Univ Vall dHebron, Vall dHebron Inst Oncol VHIO, Dept Hematol, Expt Hematol, Barcelona, Spain

[12] CIMA Univ Navarra, Inst Data Sci & Artificial Intelligence Datai, Inst Invest Sanitaria Navarra IDISNA, Computational Biol Program, Navarra, Spain

[13] Queen Mary Univ London, Ctr Genom & Computat Biol, Barts Canc Inst, London, England

[14] NYU, Sch Med, Dept Pathol, New York, NY USA

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

欧盟地平线“2020”;

关键词：

HEMATOPOIETIC STEM-CELLS; DNA MICROARRAY ANALYSIS; GENE-EXPRESSION; CD34(+) CELLS; SELF-RENEWAL; DAMAGE; IDENTIFICATION; PROFILES; FUSION;

D O I：

10.1038/s41467-022-35192-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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