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Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE141813 | GEO | 2020/02/24

REPOSITORIES: GEO

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Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [ATAC-seq]

Project description:Acute erythroid leukemia (AEL) most commonly involves transformation of both the myeloid and erythroid lineages. However, the mutations that cause AEL and the nature of the transformed cell that sustains the bi-lineage leukemia phenotype remain unknown. We here show that combined bi-alleCD45.2+LKFcgRII/III+CD55- C/EBPa and GATA-2 zinc finger 1 (ZnF1) mutations are sufficient to induce bi-lineage AEL, and that the leukemia-initiating cell has a Lin–Sca-1–c-Kit+CD150–FcyRII/III+ surface phenotype, consistent with a committed myeloid progenitor. However, we find that in the presence of bi-alleCD45.2+LKFcgRII/III+CD55- C/EBPa mutation this cell population acquires ectopic erythroid gene expression and lineage potential, leading to the formation of neomorphic neutrophil-erythroid lineage progenitors, which upon transformation generate the bi-lineage leukemia-initiating cell. These results identify C/EBPa and GATA-2 ZnF1 mutations as causative of AEL, and demonstrate that transcriptional reprogramming by a leukemia-initiating mutation can re-define the lineage output of the resulting leukemia-initiating cells.

2020-02-24 | GSE141812 | GEO

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [RNA-seq]

2020-02-24 | GSE121492 | GEO

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [10x RNA-seq]

2020-02-24 | GSE142213 | GEO

C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.

Project description:Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.

| S-EPMC7218711 | biostudies-literature

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor

Project description:Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor

| PRJNA594883 | ENA

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [RNA-seq]

Project description:Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [RNA-seq]

| PRJNA497459 | ENA

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [ATAC-seq]

Project description:Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [ATAC-seq]

| PRJNA594884 | ENA

Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [10x RNA-seq]

Project description:Combined mutation of C/EBPa and GATA-2 induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor [10x RNA-seq]

| PRJNA596226 | ENA

Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia.

Project description:Acquisition of additional genetic and/or epigenetic abnormalities other than the BCR/ABL fusion gene is believed to cause disease progression in chronic myeloid leukemia (CML) from chronic phase to blast crisis (BC). To gain insights into the underlying mechanisms of progression to BC, we screened DNA samples from CML patients during blast transformation for mutations in a number of transcription factor genes that are critical for myeloid-lymphoid development. In 85 cases of CML blast transformation, we identified two new mutations in the coding region of GATA-2, a negative regulator of hematopoietic stem/progenitor cell differentiation. A L359V substitution within zinc finger domain (ZF) 2 of GATA-2 was found in eight cases with myelomonoblastic features, whereas an in-frame deletion of 6 aa (delta341-346) spanning the C-terminal border of ZF1 was detected in one patient at myeloid BC with eosinophilia. Further studies indicated that L359V not only increased transactivation activity of GATA-2 but also enhanced its inhibitory effects on the activity of PU.1, a major regulator of myelopoiesis. Consistent with the myelomonoblastic features of CML transformation with the GATA-2 L359V mutant, transduction of the GATA-2 L359V mutant into HL-60 cells or BCR/ABL-harboring murine cells disturbed myelomonocytic differentiation/proliferation in vitro and in vivo, respectively. These data strongly suggest that GATA-2 mutations may play a role in acute myeloid transformation in a subset of CML patients.

| S-EPMC2538883 | biostudies-literature

GATA-1 directly regulates p21 gene expression during erythroid differentiation.

Project description:Lineage-determination transcription factors coordinate cell differentiation and proliferation by controlling the synthesis of lineage-specific gene products as well as cell cycle regulators. GATA-1 is a master regulator of erythropoiesis. Its role in regulating erythroid-specific genes has been extensively studied, whereas its role in controlling genes that regulate cell proliferation is less understood. Ectopic expression of GATA-1 in erythroleukemia cells releases the block to their differentiation and leads to terminal cell division. An early event in reprogramming the erythroleukemia cells is induction of the cyclin-dependent kinase inhibitor p21. Remarkably, ectopic expression of p21 also induces the erythroleukemia cells to differentiate. We now report that GATA-1 directly regulates transcription of the p21 gene in both erythroleukemia cells and normal erythroid progenitors. Using reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays, we show that GATA-1 stimulates p21 gene transcription by binding to consensus binding sites in the upstream region of the p21 gene promoter. This activity is also dependent on a binding site for Sp1/KLF-like factors near the transcription start site. Our findings indicate that p21 is a crucial downstream gene target and effector of GATA-1 during red blood cell terminal differentiation.

| S-EPMC3019278 | biostudies-literature

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