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Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [RNA-Seq]

ABSTRACT: Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [RNA-Seq]

PROVIDER: PRJNA613643 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11357400_1.fastq.gz	Fastqsanger.gz
	SRR11357400_2.fastq.gz	Fastqsanger.gz
	SRR11357500_1.fastq.gz	Fastqsanger.gz
	SRR11357500_2.fastq.gz	Fastqsanger.gz
	SRR11357401_1.fastq.gz	Fastqsanger.gz

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Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets

Project description:Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets

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Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [Bisulfite-Seq]

Project description:Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [Bisulfite-Seq]

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Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [Bisulfite-Seq]

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.

2021-02-10 | GSE147343 | GEO

Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets [RNA-Seq]

2021-02-10 | GSE147265 | GEO

Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease

Project description:Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. The clinical severity is lessened by elevated fetal hemoglobin (HbF) production in adulthood. A promising therapy is the transplantation of autologous, hematopoietic stem/progenitor cells (HSPCs) treated with CRISPR/Cas9 to downregulate the HbF repressor BCL11A via generation of double strand breaks (DSBs) in the +58-kb erythroid-specific enhancer. Here, to further enhance HbF production without increasing the mutagenic load, we targeted both +58-kb and +55-kb BCL11A erythroid-specific enhancers using base editors. We systematically dissected DNA motifs recognized by the key transcriptional activators within these regions and identified the critical nucleotides required for activator binding. Multiplex base editing of these residues was efficient and safe and generated no or little DSBs and genomic rearrangements. We observed substantial HbF reactivation, exceeding the levels achieved using the CRISPR/Cas9 nuclease-based strategy, thus efficiently rescuing the sickling phenotype. Multiplex base editing was efficient in long-term repopulating HSPCs and resulted in potent HbF reactivation in vivo. In summary, these results show that multiplex base editing of BCL11A erythroid-specific enhancers is a safe and potent strategy for treating sickle cell disease.

2025-07-28 | GSE291384 | GEO

Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets

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

2021-02-10 | GSE147344 | GEO

Exome-seq of Jak2VF erythroid progenitors cells transduced with Dnmt3a-Cas9-GFP lentivirus vs. emp-Cas9-GFP controls 17 weeks post transplantation

Project description:Exome sequencing of erythroid progenitors from Dnmt3a-Cas9-GFP+/- vs. emp-Cas9-GFP+/- controls.

2018-10-29 | E-MTAB-7243 | biostudies-arrayexpress

Multiplex genome-editing in Arabidopsis thaliana using Mb3Cas12a

Project description:The use of CRISPR/Cas proteins for the creation of multiplex genome-engineering represents an important avenue for crop improvement, and further improvements for creation of knock-in plant lines via CRISPR-based technologies may enable the high-throughput creation of designer alleles. To circumvent limitations of the commonly used CRISPR/Cas9 system for multiplex genome-engineering, we explored the use of Moraxella bovoculi 3 Cas12a (Mb3Cas12a) for multiplex genome-editing in Arabidopsis thaliana. We identified optimized promoter sequences for driving expression of single transcript multiplex crRNA arrays in A. thaliana, resulting in stable germline transmission of Mb3Cas12a-edited alleles at multiple target sites. By utilizing this system, we demonstrate single-transcript multiplexed genome-engineering using of up to 13 crRNA targets. We further show high target specificity of Mb3Cas12a-based genome-editing via whole-genome sequencing. Taken together, our method provides a simplified platform for efficient multiplex-genome-engineering in plant-based systems.

2021-09-15 | GSE162875 | GEO

In vivo CRISPR/Cas9 screen to identify candidate therapeutic gene targets to enhance docetaxel efficacy in prostate cancer

Project description:Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit due to emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure.

2020-10-07 | E-MTAB-9482 | biostudies-arrayexpress

Transcriptome of erythroid cells derived from human CD34+ cells edited at the BCL11A erythroid enahncer or at the HBG1 and HBG2 promoters using CRISPR-Cas9

Project description:BCL11A represses gamma globin expression by binding to the gamma globin gene (HBG1 and HBG2) promoters. Genome editing of the BCL11A erythroid enhancer in the intron 2 of BCL11A gene or the BCL11A binding site at the HBG1/2 promoters disrupts this pathway and leads to gamma globin induction. Transcriptomic profiling of erythroid cells derived from human CD34+ cells edited at either target site using CRISPR-Cas9 revealed broader transcriptome perturbation when edited at the BCL11A erythroid enhancer.

2024-12-10 | GSE264491 | GEO

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