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Dnmt3a regulates myeloproliferation and liver-specific homing and expansion of hematopoietic stem and progenitor cells (Bisulfite-Seq)

ABSTRACT: DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Dnmt3a ablation led to a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by marked, progressive hepatomegaly that was transplantable. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE74165 | GEO | 2016/04/24

SECONDARY ACCESSION(S): PRJNA299197

REPOSITORIES: GEO

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Dnmt3a regulates myeloproliferation and liver-specific homing and expansion of hematopoietic stem and progenitor cells (RNA-Seq)

Project description:DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Dnmt3a ablation led to a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by marked, progressive hepatomegaly that was transplantable. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.

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ASXL1 Mutations Promote Myeloid Transformation Through Loss of PRC2-Mediated Gene Repression

2012-08-21 | GSE38861 | GEO

ASXL1 Mutations Promote Myeloid Transformation Through Loss of PRC2-Mediated Gene Repression

Project description:Recurrent somatic ASXL1 mutations occur in patients with myelodysplasia (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML), and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here we identify that ASXL1 mutations result in loss of PRC2-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data we identify targets of ASXL1 repression including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the Polycomb repressive complex 2 (PRC2), and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. To assess the genome-wide effects of ASXL1 loss on chromatin state we performed chromatin immunoprecipitation followed by next generation sequencing (CHIP-seq) for histone modifications known to be associated with PcG (histone H3 lysine 27 trimethylation (H3K27me3)) or TxG activity (histone H3 lysine 4 trimethylation (H3K4me3)) in UKE1 cells expressing empty vector (EV) or 2 independent validated shRNAs for ASXL1. This Series represents the ChIP-Seq data (not the microarray data referenced in the summary above). The related micorarray data are available in GEO as GSE38692.

2012-08-21 | E-GEOD-38861 | biostudies-arrayexpress

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2013-01-17 | E-MTAB-1044 | biostudies-arrayexpress

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Evi1 governs Kdm6b-mediated histone demethylation to finely regulate the Laptm4b-driven mTORC pathway in vivo [LSK]

Project description:Ecotropic viral integration site 1 (EVI1/MECOM) overexpression is common in myeloid malignancies. We present a new Evi1 transgenic mouse model with inducible expression in hematopoietic stem cells (HSCs) and progenitor cells (HPCs) at lower levels. Upon exogenous Evi1 induction, mice displayed anemia, thrombocytopenia, lymphopenia, and dysplasia in erythroid and megakaryocyte cells with a significant expansion of committed myeloid progenitor cells, resembling human Myelodysplastic syndrome/Myeloproliferative neoplasm (MDS/MPN)-like disease. Methods: LSK cells were sorted by Sony SH800 from 3 pairs of mice transplanted with WT BM cells and Evi1-OE BM cells after pIpC injection. Around 5X103 LSK cells were harvested from each mouse. Then the cells were lysated by Trizol and total RNA was extracted by phenol-chloroform. Results: Molecular pathways altered in LSK cells from recipient mice transplanted with Evi1-OE BM cells. Conclusions: Transcription profile changed in Evi1 overexpressing hematopoietic stem and progenitor cells.

2023-06-27 | GSE235441 | GEO

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