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Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

ABSTRACT: Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function. ATAC-seq in murine c-kit+ cells for the following genotypes: Smc3 fl/+, Smc3 del/+, Flt3-ITD, Smc3 fl/del Flt3-ITD

ORGANISM(S): Mus musculus

SUBMITTER: James Bradner

PROVIDER: E-GEOD-73215 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

Project description:Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function.

2015-09-21 | GSE73215 | GEO

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [RNA-Seq]

2015-10-01 | GSE73216 | GEO

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Single Cell RNA-Seq)

Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. To identify the gene expression changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML (Single Cell RNA-Seq).

2016-03-27 | E-GEOD-77847 | biostudies-arrayexpress

Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [Methylation]

Project description:We performed genome-wide DNaseI hypersensitive site in FLT3-ITD and WT patient samples. We report corresponding gene expression, promoter methylation patterns of differential DHSs as well as differentially occupied TF binding motifs using surrounding DNAseI cut profiles. We examined association patterns of FLT3 ITD and WT AMLs and found that FLT3-ITD signaling is associated with common gene expression and chromatin signature. Examination of DNA methylation patterns in FLT3 ITD and WT AML via microarray study.

2015-07-03 | E-GEOD-64934 | biostudies-arrayexpress

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Bulk RNA-Seq)

2016-03-27 | E-GEOD-77846 | biostudies-arrayexpress

Alkynyl nicotinamides with antileukemic activity to treat poor prognosis AM

Project description:FLT3 activating mutations cause myeloproliferative neoplasms by deregulating hematopoietic progenitor cell growth, and acute myeloid leukemia is on the rise. Investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop inherent and acquired resistance to FLT3 targeted therapy. FLT3 inhibitor resistance in AML is dependent on co-occurring mutations, parallel survival pathways, and/or subsequent FLT3-ITD mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options. We identified two novel naphthyridine-based FLT3 inhibitors (HSN608 and HSN748) that specifically target FLT3-ITD at sub-nanomolar concentrations and are effective against drug-resistant secondary mutations. In the current study, we evaluated these compounds antileukemic activity against FLT3-ITD and gatekeeper mutations in drug-resistant AML, relapsed/refractory AMLs with FLT3 mutations, and in vivo mouse models with combinations of epigenetic mutations TET2 with FLT3-ITD, and AML patients PDX. In these model systems, we demonstrate that HSN748 outperforms the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3-ITD.

2022-12-07 | MSV000090855 | MassIVE

Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [Agilent]

Project description:We performed genome-wide DNaseI hypersensitive site in FLT3-ITD and WT patient samples. We report corresponding gene expression, promoter methylation patterns of differential DHSs as well as differentially occupied TF binding motifs using surrounding DNAseI cut profiles. We examined association patterns of FLT3 ITD and WT AMLs and found that FLT3-ITD signaling is associated with common gene expression and chromatin signature. Examination of gene expression patterns in FLT3 ITD and WT AML via microarray study.

2015-07-03 | E-GEOD-64873 | biostudies-arrayexpress

Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [DNAse-Seq]

Project description:We performed genome-wide DNaseI hypersensitive site in FLT3-ITD and WT patient samples. We report corresponding gene expression, promoter methylation patterns of differential DHSs as well as differentially occupied TF binding motifs using surrounding DNAseI cut profiles. We examined association patterns of FLT3 ITD and WT AMLs and found that FLT3-ITD signaling is associated with common gene expression and chromatin signature. Examination of genome-wide DNaseI hypersensitivite sites in FLT3 ITD and WT AML.

2015-07-03 | E-GEOD-64864 | biostudies-arrayexpress

Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [ChIP-Seq]

2015-07-03 | E-GEOD-64862 | biostudies-arrayexpress

Smc3 regulates B-cell transit through germinal centers and restricts their malignant transformation (HiC)

Project description:During the germinal center (GC) reaction, B-cells undergo extensive redistribution of cohesin complex and 3D re-organization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that conditional homozygous deletion of cohesin subunit Smc3 abrogated GC formation, yet in marked contrast, Smc3 haploinsufficiency induced GC hyperplasia, skewing of GC polarity and impaired plasma cell differentiation. Transcriptional and architectural profiling revealed defects in GC terminal differentiation programs controlled by lymphoma epigenetic tumor suppressors Tet2 and Kmt2d, and failure of Smc3+/- GC B-cells to switch from B-cell to plasma cell lineage factors. There was also impaired connectivity of gene regulatory elements controlling tumor suppressor genes, and accordingly Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose dependent function for cohesin in humoral immunity to facilitate the B-cell to plasma cell lineage switch, while restricting their malignant transformation.

2020-10-13 | GSE143853 | GEO

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