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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 [10x RNA-seq]

ABSTRACT: 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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE142213 | 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 [RNA-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.

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Project description:Acute erythroid leukemia (AEL) is a high-risk leukemia with a distinct mutational spectrum. Here, we examined the cooperativity of loss of function alterations in leukemogenesis and tested the therapeutic tractability of each model of AEL. Using CRISPR/Cas9 genome editing, we generated six pools of lentiviral vectors with different combinations of guide RNAs and transduced Cas9-eGFP-mouse mouse hematopoietic stem and progenitor cells (HSPCs) that were used in transplant assays. Induced tumors were characterized by phenotype, genomic/epigenomic analysis and tested for sensitivity to 222 therapeutic agents. Tumor genotype determined tumor phenotype with Bcor and Tp53 driving erythroid leukemogenesis. Tumors showed acquisition of additional somatic mutations during serial passaging and by transcriptomic analysis AEL models had overexpression of transcription factors required for differentiation of megakaryocyte-erythroid progenitors and recapitulated human AEL. Dnmt3a-mutated models exhibited global hypomethylation, but hypermethylation when co-occurred with Tet2 mutations. Drug response was associated with genotype. Tp53 wild-type but Dnmt3a/Tet2 double mutant cells were the most chemo-sensitive models. ViceversaTp53-mutated AEL subtypes were chemo-resistant to several conventional chemotherapeutics but highly sensitivity to PARP inhibitors, including talazoparib. Sensitivity to talazoparib was confirmed in vivo when combined with decitabine. In conclusion, combinations of recurrently mutated genes are critical determinants of leukemia phenotype, with central roles of Tp53 and Bcor mutations in driving the erythroid leukemogenesis. Using these models as preclinical tools, we have shown the potential for bromodomain and PARP inhibition as new therapeutic strategies in AEL.

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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

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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 [RNA-seq]

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Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

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