Project description:Apoptosis Repressor with Caspase Recruitment Domain (ARC) was recently found to be highly expressed in solid tumors and in blast cells of patients with acute myeloid leukemia (AML). In this study, we assessed the functional and molecular consequences of loss of ARC on the hematopoietic system. We found, unexpectedly, that deletion of Nol3 (the gene that encodes ARC) in mice leads to development of a myeloproliferative neoplasm (MPN) resembling primary myelofibrosis (PMF). Nol3-/--induced MPN is transplantable into secondary recipient mice and is characterized by anemia, thrombocytopenia, extramedullary hematopoiesis, and bone marrow fibrosis. Despite an overall reduction in bone marrow cellularity Nol3-/- MPN mice have an expanded Thy1+LSK stem cell population with increased cell cycling, in addition to a myelomonocytic differentiation bias. Molecularly, the Nol3-/--induced phenotype is, at least in part, mediated by activation of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) and MYC. Nol3-/- MPN Thy1+LSK cells show significant molecular similarities with primary CD34+ cells isolated from patients with PMF. Furthermore, we found that Nol3 is deleted in patients with human myeloid malignancies and has decreased expression in a subset of patients with de novo AML. Our results reveal a novel role of Nol3 in normal hematopoiesis and in the pathogenesis of myeloid malignancies. To obtain insight into the molecular mechanism of the Nol3-/- -induced MPN, we performed gene expression profiling on Thy1+LSK bone marrow cells from Nol3+/+ and Nol3-/- MPN mice
Project description:In BRE-GFP transgenic mice BMP activated cells are marked by GFP expression. Analysis of GFP+ and GFP- LSK-SLAM HSC enriched fractions from fetal liver and adult bone marrow shows the interinsic differences in the genetic program of these two HSC enriched fractions. RNAseq of GFP+ and GFP- LSK-SLAM cells from BRE-GFP transgenic mice Fetal liver and adult bone marrow
Project description:ATAC-seq profiling of Nfat5 KO and wild type macrophages derived from bone marrow (primary cells), treated or not with Lipopolysaccharide (LPS).
Project description:To evaluate the DNA methylation in LSK cells from the bone marrow of wildtype or Tet2/3 DKO mice. In order to address the impact of the loss of Tet2/3 proteins in DNA methylation in LSK cells, we compared by WGBS the methylome of wild and, Tet2/3 DKO LSK cells in bone marrow.
