Expression data of mRNA/LncRNA from megakaryocytes in MLL-AF9 AML mouse versus healthy control bone marrow
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112942 | GEO | 2020/06/25
REPOSITORIES: GEO
Similar Datasets
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 hematopoietic system gives rise to a heterogeneous population of terminally differentiated cells that reside in the bone marrow (BM) to fulfill their roles in immunity, blood clotting and tissue oxygenation. Hematopoietic stem and progenitor cells are at the apex of a hierarchically organized maturation cascade constantly replenishing the pool of differentiated cells to maintain blood cell homeostasis. The bone marrow microenvironment is functionally compartmentalized by heterogeneous niche cells that provide physical and soluble signals to spatio-temporally organize hematopoiesis. Megakaryocytes (MKs) are niche cells of hematopoietic origin that support hematopoietic stem cell (HSCs) homeostasis and generate circulating platelets. Platelet production involves the release of MK fragments while their cell body is entirely consumed in a process termed thrombopoiesis. Consequently, replenishment of fragmented MKs from MK progenitors (termed megakaryopoiesis) is required to ensure sufficient platelet production, but also to maintain MK homeostasis within the HSC niche. Here, we used intravital imaging of the megakaryocytic lineage to identify the spatio-temporal patterns of megakaryopoiesis during steady state and thrombocytopenia. We show that MK consumption during thrombopoiesis is compensated by immediate and local proliferation of MK progenitors. MK homeostasis is controlled by plasmacytoid dendritic cells (pDCs) that scan the BM and secrete Interferon alpha (INFa) upon detection of exhausted megakaryocytes to trigger megakaryopoiesis. We identified local pDC-derived INFa release as a physiological inflammatory stimulus of the bone marrow niche that synchronizes megakaryopoiesis and thrombopoiesis to maintain homeostasis of MKs and platelets in steady state and under stress. Viral infection with SARS-CoV-2 can manipulate pDC-driven MK proliferation leading to inappropriate megakaryopoiesis, which has been associated with thrombotic complications during COVID-19.
2024-04-26 | GSE185488 | GEO
Project description:Immune thrombocytopenia (ITP) is a common platelet disorder in pediatric patients. Pediatric and adult ITP have been associated with sialic acid alterations, but the pathophysiology of ITP remains elusive, and ITP is often a diagnosis of exclusion. Our analysis of pediatric ITP plasma samples showed increased anti-Thomsen-Friedenreich antigen (TF-antigen) antibody representation, suggesting increased exposure of the typically sialylated and cryptic TF-antigen in these patients. The O-glycan sialyltransferase St3gal1 add sialic acid specifically on the TF-antigen. To understand if TF-antigen exposure associates with thrombocytopenia, we generated a mouse model with targeted deletion of St3gal1 in megakaryocytes (MK) (St3gal1MK-/-). TF-antigen exposure was restricted to MKs and resulted in thrombocytopenia. Deletion of Jak3 in St3gal1MK-/- mice normalized platelet counts implicating involvement of immune cells. Interferon-producing Siglec H-positive bone marrow (BM) immune cells engaged with O-glycan sialic acid moieties to regulate type I interferon (IFN-I) secretion and platelet release (thrombopoiesis), as evidenced by partially normalized platelet count following and inhibition of interferon and Siglec H receptors. Single cell RNAseq determined that TF-antigen exposure by MKs primed St3gal1MK-/- BM immune cells to release IFN-I. Single cell RNAseq further revealed a new population of immune cells with a plasmacytoid dendritic cell (pDC)-like signature and concomitant upregulation of immunoglobulin re-arrangement gene transcripts Igkc and Ighm, suggesting additional immune regulatory mechanisms. Thus, aberrant TF-antigen moieties, often found in pathological conditions, regulate immune cells and thrombopoiesis in the BM, leading to reduced platelet count.
2021-06-29 | GSE179067 | GEO
Project description:High ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of hematopoietic stem cells (HSC) and are responsible for platelet formation. Using a mouse knockout model with normal megakaryocyte numbers but essentially devoid of LCM (MK-LCM KO), we demonstrated a pronounced increase in bone marrow HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. When HSC isolated from a MK-LCM KO microenvironment were transplanted in lethally irradiated mice, the absence of LCM increased HSC in BM, blood and spleen. Severe thrombocytopenia was observed in animals with diminished LCM, although there was no change in megakaryocyte ploidy distribution. In contrast, WT HSC-generated LCM regulated a normal HSC pool and prevented thrombocytopenia. The present label-free quantitative LC-MSMS data was used to determine proteins that are differentially expressed in bone marrow cells of MK-LCM WT versus MK-LCM KO mice.
2023-05-10 | PXD040423 | Pride
Project description:Thioredoxin-interacting protein (TXNIP) is ubiquitously expressed in blood cells, including hematopoietic stem cells (HSCs), monocytes, and platelets. Here we report a novel finding that TXNIP plays a crucial role in megakaryopoiesis and platelet biogenesis via interacting with GATA1, a transcription factor for megakaryocyte-erythroid differentiation. Txnip-/- mice displayed immature megakaryocytes in the bone marrow with thrombocytopenia, which had gotten worse as the mice aged. Transcriptome analysis revealed that the transcriptional activity of GATA1 was significantly enhanced in the Txnip-/- megakaryocyte precursors (MkPs) than wild type (WT) cells. During megakaryopoiesis in ex vivo, Txnip-/- MkPs remained small in cell size with less mitochondrial mass, and more glycolysis for ATP production, as opposed to the normal megakaryocyte maturation. The effects of TXNIP in megakaryocytes were recapitulated in human cord blood CD34+ HSC-derived differentiation. Taken together, this study demonstrates the importance of spatiotemporal expression of TXNIP in platelet biogenesis. We propose for the first time that TXNIP might play a critical role in determining a lineage between megakaryocytes and erythroid cells from a common megakaryocyte-erythroid progenitor via regulation of transcriptional activity of GATA1.
2022-12-31 | GSE186400 | GEO
Project description:Adult and fetal megakaryocytes are morphologically different. These differences contribute to neonatal thrombocytopenia in premature neonates and in neonates after infection and also contribute to poor megakaryocytes engraftment after umbilical cord blood transplant. We found that Dyrk1a kinase inhibition shift the fetal megakaryocytes phenotype toward adult phenotype. This effect is mediated by MKL1 the master regulator of megakaryocytes morphogenesis. To identify differences between adult and fetal megakaryocytes we performed RNA seq of adult derived megakaryocytes and fetal derived megakaryocytes treated and untreated with Dyrk inhibitors. Through this approach we identified cohorts of genes co-regulated in adult megakaryocytes and fetal megakaryocytes treated with the dyrk inhibitors. More importantly, we found that the dyrk inhibition in fetal megakaryocytes leads to upregulation of a significant number of MKL1 target genes.
2022-05-29 | GSE204909 | GEO
Project description:Adult and fetal megakaryocytes are morphologically different. These differences contribute to neonatal thrombocytopenia in premature neonates and in neonates after infection and also contribute to poor megakaryocytes engrafment after umbilical cord blood transplant. We found that Dyrk1a kinase inhibition shift the fetal megakaryocytes phenotype toward adult phenotype. This effect is mediated by MKL1 the master regulator of megakaryocytes morphogenesis. To identify deferences between adult and fetal megakaryocytes we performed RNA seq of adult derived megakaryocytes and fetal derived megakaryocytes treated and untreated with Dyrk inhibitors. Through this approach we identified cohorts of genes co-regulated in adult megakaryocytes and fetal megakaryoctes treated with the dyrk inhibitors. More importantly, we found that the dyrk inhibition in fetal megakaryocytes leads to upregulation of a significant number of MKL1 target genes.
2022-08-30 | GSE195671 | GEO
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.
2019-01-25 | PXD009020 | Pride
Project description:The Stem Cell Leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1 and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, Lymphoblastic Leukemia 1 (Lyl1) might explain this observation. To determine if Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking one or both factors in megakaryocytes. Conditional Scl knockout mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4SclcKO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4SclcKO mice generated on a Lyl1-null background (double knockout, DKO mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation and markedly impaired platelet aggregation. DKO megakaryocytes, but not single knockouts, had reduced expression of Gata1, Fli1, Nfe2 and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production and function by regulating expression of partner proteins including Gata1 and Fli1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations as a cause of inherited thrombocytopenia.
2020-12-21 | GSE125025 | GEO
Project description:The transcription factor Growth Factor Independence 1B (GFI1B) recruits Lysine Specific Demethylase 1A (LSD1/KDM1A) to stimulate gene programs relevant for megakaryocyte and platelet biology. Inherited pathogenic GFI1B variants result in thrombocytopenia and bleeding propensities with varying intensity. Whether these affect similar gene programs is unknow. Here we studied transcriptomic effects of four patient-derived GFI1B variants (GFI1BT174N,H181Y,R184P,Q287*) in MEG01 megakaryoblasts. Compared to normal GFI1B, each variant affected different gene programs with GFI1BQ287* uniquely failing to repress myeloid traits. In line with this, single cell RNA-sequencing of induced pluripotent stem cell (iPSC)-derived megakaryocytes revealed a 4.5-fold decrease in the megakaryocyte/myeloid cell ratio in GFI1BQ287* versus normal conditions. Inhibiting the GFI1B-LSD1 interaction with small molecule GSK-LSD1 resulted in activation of myeloid genes in normal iPSC-derived megakaryocytes similar as observed for GFI1BQ287* iPSC-derived megakaryocytes. Thus, GFI1B and LSD1 facilitate gene programs relevant for megakaryopoiesis while simultaneously repressing programs that induce myeloid differentiation.
2024-03-28 | PXD050401 | Pride