In vivo expression of mutant Samd9l collaborates with inflammation to induce bone marrow failure
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ABSTRACT:
PROVIDER: PRJNA789872 | ENA |
REPOSITORIES: ENA
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Project description:In vivo expression of mutant Samd9l collaborates with inflammation to induce bone marrow failure. [RNA-Seq]
| PRJNA787569 | ENA
Project description:SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have hypocellular bone marrows and a greater risk of developing clonal chromosome 7 deletions. We recently demonstrated that expressing SAMD9/SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces apoptosis. Here we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. We showed that mutant Samd9l cells are less fit relative to wild-type counterparts, which is exacerbated by inflammatory stimuli, and ultimately leads to marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with germline SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-b as a potential causative and targetable networkpathway. Further, we observed non-random genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking the pathologic features observed in patients.
2022-10-08 | GSE191147 | GEO
Project description:SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have hypocellular bone marrows and a greater risk of developing clonal chromosome 7 deletions. We recently demonstrated that expressing SAMD9/SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces apoptosis. Here we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. We showed that mutant Samd9l cells are less fit relative to wild-type counterparts, which is exacerbated by inflammatory stimuli, and ultimately leads to marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with germline SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-b as a potential causative and targetable networkpathway. Further, we observed non-random genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking the pathologic features observed in patients.
2022-10-08 | GSE190566 | GEO
Project description:Inherited Bone Marrow Failure Syndromes
| PRJNA417130 | ENA
Project description:Inherited Bone Marrow Failure Syndromes
| PRJNA417131 | ENA
Project description:Background and methods: Ruxolitinib (RUX), a Jak1/2 inhibitor, has been reported to attenuate murine bone marrow failure recently. Its potential toxocicty of anemia and thrombocytopenia in human remains a concern. To minimize its potential toxoxicity, we tested therapeutic effectsof low dose ruxolitinib plus cyclosporine in murine model of immune-mediated bone marrow failure. Bone marrow CD8 and CD4 T cells were sorted from treated or untreated bone marrow failure mice. RNA-Seq and analysis was performed using SMART-Seq mRNA LP Kit (Takara) and the Illumina Novaseq6000, according to the Institute's protocols. Results: low dose of ruxolitinib plus cyclosporine improved pancytopenia and BM cellularity and decreased BM T cell infiltration in bone marrow failure mice. RNA sequencing demonstrated that low dose of ruxolitinib plus cyclosporine suppressed immune-related pathways in bone marrow infiltrated CD8 T cells and MHC-II expression in CD4 T cells compared with untreated mice. Conclusion: Our results demonstrate that low dose of ruxolitinib plus cyclosporine remains the efficacy in attenuation of disease and extending survival of immune-mediated bone marrow failure mice.
2024-05-08 | GSE240864 | GEO
Project description:Background and methods: Ruxolitinib (RUX) is a Jak inhibitor that is used in the treatment of intermediate or high risk myelofibrosis and resistant forms of polycythemia vera and graft-vs-host disease due to its efficacy of reducing inflammatory cytokines and markers of inflammation. We tested its potential therapeutic effects in murine models of immune-mediated bone marrow failure. RNA-Seq and analysis was performed using NEBNext Ultra™ II RNA Library Prep Kit for Illumina and Illumina Novaseq6000, according to the Institute's protocols. Results: As both prophylaxis and therapy, Ruxolitinib improved pancytopenia and BM cellularity and decreased BM T cell infiltration in bone marrow failure mice. RNA sequencing demonstrated that Ruxolitinib suppressed expression of inflammtory genes in bone marrow infiltrated CD8 T cells compared with untreated mice. Conclusion: Our results demonstrate that Ruxolitinib is highly effective in attenuation of disease and extending survival of immune-mediated bone marrow failure mice.
2023-01-29 | GSE196645 | GEO
Project description:Background and methods: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which originate in the bone marrow (BM) and have immunoregulatory functions. MDSCs have been implicated in the pathogenesis of several autoimmune diseases but not in immune aplastic anemia (AA). We examined the roles of granulocytic-MDSCs (G-MDSCs) in murine models of human AA and bone marrow failure (BMF). To perform Totalseq, bone marrow mononuclear cells were FACS sorted to obtain alive cells based on FSC and SSC from five bone marrow failure control mice and five G-MDSC-treated mice, mRNA profiles of single cells were generated and sequenced on an Illumina Novaseq System. Results: As both prophylaxis and therapy, BM-derived G-MDSCs improved pancytopenia and BM cellularity and decreased BM T cell infiltration in major histocompatibility (MHC)-matched CB10 BMF mice. Single cell RNA sequencing demonstrated that G-MDSCs downregulated cell cycle related pathways in BM infiltrated T cells, consistent with suppression of T cell proliferation by G-MDSCs. Conclusion: Our results demonstrate that BM-derived G-MDSCs improved pancytopenia and BM cellularity and decreased BM T cell infiltration in major histocompatibility (MHC)-matched CB10 BMF mice, but not in MHC-mismatched CByB6F1 BMF model. Therapeutic efficacy of G-MDSCs are immune context-dependent. Bone marrow mononuclear cells were FACS sorted to obtain alive cells based on FSC and SSC from five bone marrow failure control mice and five G-MDSC-treated mice.
2022-07-27 | GSE193421 | GEO
Project description:We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1 production partially prevents the post-myocardial infarction loss of type H vasculature in mice.
2021-05-13 | E-MTAB-10448 | biostudies-arrayexpress
Project description:We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1 production partially prevents the post-myocardial infarction loss of type H vasculature in mice.
2021-05-11 | E-MTAB-10432 | biostudies-arrayexpress