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Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation

ABSTRACT: Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation

PROVIDER: PRJNA326945 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3721890.fastq.gz	Fastqsanger.gz
	SRR3721900.fastq.gz	Fastqsanger.gz
	SRR3721891.fastq.gz	Fastqsanger.gz
	SRR3721901.fastq.gz	Fastqsanger.gz
	SRR3721892.fastq.gz	Fastqsanger.gz

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Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation (BiSulfite-seq)

Project description:DNA methylation analysis of T-cell acute lymphoblastic leukemia blast cells from either control mice or Dnmt3a knockout mice carrying a Notch1 Intracellular Domain (NICD) retrovirus

2017-07-14 | GSE83759 | GEO

Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation (RNA-seq)

Project description:Gene expression analysis of T-cell acute lymphoblastic leukemia blast cells from either control mice or Dnmt3a knockout mice carrying a Notch1 Intracellular Domain (NICD) retrovirus

2017-07-14 | GSE83755 | GEO

Dnmt3a regulates T-cell development and suppresses T-ALL transformation.

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises ~15% and 25% of pediatric and adult ALL cases, respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus, which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.

| S-EPMC5636646 | biostudies-literature

SMTNL1 Regulates Development and Metabolic Transformation of Skeletal Muscle in Hyperthyroidism

Project description:SMTNL1 Regulates Development and Metabolic Transformation of Skeletal Muscle in Hyperthyroidism

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Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation

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

2017-07-14 | GSE83769 | GEO

Mus musculus

Project description:Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation (BiSulfite-seq)

| PRJNA326943 | ENA

Mus musculus

Project description:Dnmt3a Regulates T-cell Development and Suppresses T-ALL Transformation (RNA-seq)

| PRJNA326939 | ENA

Selection Pressures in the Aged Microenvironment Drive Transformation of Dnmt3a-Mutant Hematopoietic Stem Cells to Myeloid Malignancy

Project description:Driver somatic mutations in adult acute myeloid leukemia (AML) are often preceded by a benign or premalignant state termed clonal hematopoiesis (CH) for which the greatest risk factor is aging. To risk-stratify aged individuals and develop therapies to prevent AML, we need to understand the variables that promote transformation from CH to AML. Using our orthogonally inducible Dnmt3aR878H;Npm1cA-mutant model of progression from CH to myeloid malignancy, we find that in young mice, Dnmt3a mutation buffers against myeloid differentiation, proliferation, acquisition of cooperating mutations and transformation induced by stress, inflammation, and the oncogenic Npm1 mutation. However, when Dnmt3a;Npm1-mutant hematopoietic stem cells (HSCs) are transplanted into naturally aged recipient mice, they gain myeloid-biased differentiation capacity and have an accelerated transformation to AML. These results support the hypothesis that alterations in the aged microenvironment drive risk of AML in individuals with CH and help to explain why this Dnmt3a mutation is exceedingly rare in pediatric leukemias.

2021-07-15 | GSE180116 | GEO

Expression analysis of DNMT3A mutant-transduced hematopoetic stem/progenitors

2016-02-10 | GSE55262 | GEO

Expression analysis of DNMT3A mutant-transduced hematopoetic stem/progenitors

Project description:Despite the impact of DNMT3A mutation in acute myeloid leukemia has been emphasized, the precise molecular mechanisms in leukemogenesis are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant hematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are down-regulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells. DNMT3A mutant also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), leading to transcriptional silencing of PU.1. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. Taken together, our results highlight the functional role of DNMT3A mutation, forming the basis for leukemia development. GFP-labeled empty vector, DNMT3A wild-type (WT), R882H-transduced LSK cells derived from transplanted mice were utilized for compared the expression profiles (3 sorted empty vector-transduced LSK cells, 3 sorted DNMT3A WT-transduced LSK cells, and 3 sorted DNMT3A R882H-transduced LSK cells. Total RNA was extracted by TaKaRa NucleoSpin RNA XS according to the manufacturerâs protocol. Amplification and biotin labeling of fragmented cDNA was carried out from 3.67 ng of total RNA by using NuGen Ovation Pico WTA System V2 (NuGEN) and SureTag Complete DNA Labeling Kit (Agilent). Each 2 Î¼g of cDNA were hybridized to the Agilent SurePrint G3 Mouse Gene Expression 8x60K (Agilent) using Gene Expression Hybridization Kit (Agilent). After scanning, the signal intensity for each feature was measured by Agilent Feature Extraction (Agilent).

2016-02-10 | E-GEOD-55262 | biostudies-arrayexpress

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