Gene expression signature of Anagrelide in megakaryocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60621 | GEO | 2017/08/16
SECONDARY ACCESSION(S): PRJNA258658
REPOSITORIES: GEO
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Project description:Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes (MKs) by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFN- to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for MK and platelet homeostasis in steady state and stress. However, excessive activation of pDCs, such as by viral infections, can disturb this homeostatic circuit. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis. Together, we uncover a hitherto unknown pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain tissue homeostasis of the megakaryocytic lineage.
2024-05-01 | GSE261996 | GEO
Project description:The role of ABCC4, an ATP-binding cassette transporter, in the process of platelet formation, megakaryopoiesis, is unknown. Here, we show that ABCC4 is highly expressed in megakaryocytes (MKs). Mining of public genomic data (ATAC-seq and genome wide chromatin interactions, Hi-C) revealed that key megakaryopoiesis transcription factors (TFs) interacted with ABCC4 regulatory elements and likely accounted for high ABCC4 expression in MKs. Importantly these genomic interactions for ABCC4 ranked higher than for genes with known roles in megakaryopoiesis suggesting a role for ABCC4 in megakaryopoiesis. We then demonstrate that ABCC4 is required for optimal platelet formation as in vitro differentiation of fetal liver derived MKs from Abcc4-/- mice exhibited impaired proplatelet formation and polyploidization, features required for optimal megakaryopoiesis. Likewise, a human megakaryoblastic cell line, MEG-01 showed that acute ABCC4 inhibition markedly suppressed key processes in megakaryopoiesis and that these effects were related to reduced cAMP export and enhanced dissociation of a negative regulator of megakaryopoiesis, protein kinase A (PKA) from ABCC4. PKA activity concomitantly increased after ABCC4 inhibition which was coupled with significantly reduced GATA-1 expression, a TF needed for optimal megakaryopoiesis. Further, ABCC4 protected MKs from 6-mercaptopurine (6-MP) as Abcc4-/- mice show a profound reduction in MKs after 6-MP treatment. In total, our studies show that ABCC4 not only protects the MKs but is also required for maximal platelet production from MKs, suggesting modulation of ABCC4 function might be a potential therapeutic strategy to regulate platelet production.
2024-01-05 | GSE234560 | GEO
Project description:The role of ABCC4, an ATP-binding cassette transporter, in the process of platelet formation, megakaryopoiesis, is unknown. Here, we show that ABCC4 is highly expressed in megakaryocytes (MKs). Mining of public genomic data (ATAC-seq and genome wide chromatin interactions, Hi-C) revealed that key megakaryopoiesis transcription factors (TFs) interacted with ABCC4 regulatory elements and likely accounted for high ABCC4 expression in MKs. Importantly these genomic interactions for ABCC4 ranked higher than for genes with known roles in megakaryopoiesis suggesting a role for ABCC4 in megakaryopoiesis. We then demonstrate that ABCC4 is required for optimal platelet formation as in vitro differentiation of fetal liver derived MKs from Abcc4-/- mice exhibited impaired proplatelet formation and polyploidization, features required for optimal megakaryopoiesis. Likewise, a human megakaryoblastic cell line, MEG-01 showed that acute ABCC4 inhibition markedly suppressed key processes in megakaryopoiesis and that these effects were related to reduced cAMP export and enhanced dissociation of a negative regulator of megakaryopoiesis, protein kinase A (PKA) from ABCC4. PKA activity concomitantly increased after ABCC4 inhibition which was coupled with significantly reduced GATA-1 expression, a TF needed for optimal megakaryopoiesis. Further, ABCC4 protected MKs from 6-mercaptopurine (6-MP) as Abcc4-/- mice show a profound reduction in MKs after 6-MP treatment. In total, our studies show that ABCC4 not only protects the MKs but is also required for maximal platelet production from MKs, suggesting modulation of ABCC4 function might be a potential therapeutic strategy to regulate platelet production.
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2009-01-31 | GSE14478 | GEO
Project description:Platelets have a wide range of functions including critical roles in hemostasis, thrombosis, and immunity. We hypothesized that during acute inflammation, such as in life-threatening sepsis, there are fundamental changes in the sites of platelet production and phenotypes of resultant platelets. Here, we showed during sepsis that the spleen is a major site of megakaryopoiesis and platelet production. Sepsis provoked an adrenergic-dependent mobilization of megakaryocyte-erythrocyte progenitors (MEPs) from the bone marrow to the spleen where interleukin-3 (IL-3) induced their differentiation into megakaryocytes. In the spleen, immune-skewed megakaryocytes produced a CD40L-high platelet population with potent immunomodulatory functions. Transfusions of post-sepsis platelets enriched from splenic production enhanced immune responses and reduced overall mortality in sepsis-challenged animals. These findings identify a spleen-derived protective platelet population that may be broadly immunomodulatory in acute inflammatory states such as sepsis.
2022-02-14 | GSE196607 | GEO
Project description:Thrombocytopenia is a major and fatal complication for AML, while what happened to megakaryopoiesis and thrombopoiesis in AML remains unknown. Megakaryocytes have been recognized as essential HSC niche cells for their function to maintain HSC quiescence and support HSC regeneration. Megakaryocytes are robustly affected in AML bone marrow, while the alterations of their platelet-releasing and HSC supportive function are incompletely understood.
2020-06-25 | GSE112942 | GEO
Project description:Menin inhibition, an approved therapy for MLL-rearranged acute myeloid leukemia, is accompanied by decreased platelet counts in 15-20% of heavily pre-treated leukemia patients. While studying the mechanism that accounts for this effect, we discovered that menin inhibition reduced the numbers of megakaryocyte progenitors in human CD34+ cultures and in mice. Given this ability to suppress megakaryopoiesis, which is a key driver of myeloproliferative neoplasms (MPN), we investigated the extent to which menin inhibition ameliorates MPN phenotypes. We found that the menin inhibitor revumenib has potent anti-tumor activity in MPN animal models, leading to significantly increased survival, decreased accumulation of megakaryocytes, normalization of peripheral blood counts, and ablation of bone marrow fibrosis. Revumenib also synergized with the JAK inhibitor ruxolitinib while having subtle effects in healthy mice. Moreover, revumenib suppressed megakaryopoiesis of primary MPN patient specimens in colony forming assays and liquid culture. Importantly, knockout of menin and its target MEIS1 phenocopied the action of revumenib, confirming an on-target effect of the drug. Of note, menin inhibition was not associated with suppression of JAK/STAT signaling indicating that it is a novel dependency. Together we reveal that menin inhibition is a novel therapeutic approach for MPNs.
2026-07-09 | GSE309082 | GEO
Project description:Human embryonic stem cells (hESCs) have become an ideal cell source for the ex vivo generation of megakaryocyte (MK) and platelet products for clinical applications. However, an ongoing challenge is to establish scalable culture systems to maximize the yield of stem cell-derived MKs that release platelets. We defined a specific dynamic 3D manufacturing system that could remarkably facilitate megakaryopoiesis and increase the yield of platelet-producing MKs from hESCs within a 12-day induction period. Additionally, an increased number of > 16N ploidy MKs, proplatelets, and platelets were generated from induced cells harvested on day 12 using the specific dynamic culture method. The specific dynamic culture method significantly enhanced endothelium-to-hematopoietic transition and early hematopoiesis. More importantly, MK fate was significantly facilitated in a specific dynamic manner during early hematopoiesis. Mechanistically, this dynamic culture significantly enhanced mitochondrial function via the oxidative phosphorylation pathway and caused differentiation skewing of hESCs toward megakaryopoiesis. We defined a specific dynamic culture system in a baffled-flow manner that enabled the mass production of MKs from hESCs within 12 days. This study can aid in the automatic and scalable production of MKs from stem cells using baffled-flow bioreactors and assist in the manufacturing of hESC-derived MK and platelet products.
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Project description:Dominant-negative mutations in transcription factor Growth Factor Independence-1B (GFI1B) cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that normal and mutant GFI1B interacted most strongly with the LSD1-RCOR-HDAC corepressor complex in megakaryoblasts. Sequestration of this complex by mutant GFI1B and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B-mutant induced pluripotent stem cells (iPSC) also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant iPSC-derived megakaryocytes identified a multitude of deregulated pathways downstream of mutant GFI1B. Proteome studies on primary normal and GFI1B-mutant platelets showed reduced expression of proteins implicated in platelet function, and sustained expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B regulates a broad developmental program during megakaryopoiesis. Mutant GFI1B deregulates this program through LSD1-RCOR-HDAC sequestering.
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Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes. C-kit+CD41+ megakaryocyte progenitors from PF4-Cre/SRF C57BL/6 SRF WT (3) and C57BL/6 SRF KO (3) mice were sorted by flow cytometry and cultured for three days in thrombopoietin.
2010-07-13 | E-GEOD-21859 | biostudies-arrayexpress