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The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183328 | GEO | 2022/11/10

REPOSITORIES: GEO

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The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [Young_Elderly_MDS]

Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis with increased incidence in elderly individuals. Genetic alterations do not fully explain the molecular pathogenesis of the disease, indicating that other types of lesions may play a role in its development. In this work, we analyzed the transcriptional lesions of human HSCs, demonstrating how aging and MDS are characterized by a complex transcriptional rewiring that manifests as diverse linear and non-linear transcriptional dynamisms. While aging-associated lesions seemed to predispose elderly HSCs to myeloid transformation, disease-specific alterations may be involved in triggering MDS development. Among MDS-specific lesions, we detected the overexpression of the transcription factor (TF) DDIT3. Exogenous upregulation of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis, with an accumulation of cells in early stages of erythroid differentiation, as determined by single-cell RNA-sequencing. Increased DDIT3 expression was associated with downregulation of transcription factors required for normal erythropoiesis, such as KLF1, TAL1 or SOX6, and with a failure in the activation of their erythroid transcriptional programs. Finally, DDIT3 knockdown in CD34+ cells from MDS patients was able to restore erythropoiesis, as demonstrated by immunophenotypic and transcriptional profiling. These results demonstrate that DDIT3 may be a driver of MDS transformation, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing these patients.

2022-11-10 | GSE183325 | GEO

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [overexpression_and_knockdown]

2022-11-10 | GSE183327 | GEO

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [scRNA-Seq]

2022-11-10 | GSE183326 | GEO

Protein Array Screening of Myelodysplastic Syndromes

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-11-21 | E-GEOD-48155 | biostudies-arrayexpress

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes

Project description:The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes

| PRJNA759927 | ENA

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [overexpression_and_knockdown]

Project description:The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [overexpression_and_knockdown]

| PRJNA759930 | ENA

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [Young_Elderly_MDS]

Project description:The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [Young_Elderly_MDS]

| PRJNA759928 | ENA

The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [scRNA-Seq]

Project description:The transcription factor DDIT3 is a Potential Driver of Dyserythropoiesis in Myelodysplastic Syndromes [scRNA-Seq]

| PRJNA759931 | ENA

Protein Array Screening of Myelodysplastic Syndromes

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-11-21 | GSE48155 | GEO

Clinical and biological implications of driver mutations in myelodysplastic syndromes.

Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.

| S-EPMC3837510 | biostudies-other

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