CAR virus receptor mediates erythroid differentiation and migration and is downregulated in MDS
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ABSTRACT:
PROVIDER: PRJNA622679 | ENA |
REPOSITORIES: ENA
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Project description:The major Coxsackie-Adenovirus receptor, CAR, is specifically down-regulated in immature erythroid progenitor cells in patients with MDS CAR mediates erythroid maturation in progenitor cells and their migration which may explain the maturation defect and pathology in MDS
2021-12-01 | GSE147963 | GEO
Project description:Myelodysplastic syndromes (MDS) are myeloid neoplasms presenting with dysplasia in the bone marrow (BM) and peripheral cytopenia. In most patients anemia develops. We screened for genes that are expressed abnormally in erythroid progenitor cells (EP) and contribute to the pathogenesis of MDS. We found that the Coxsackie-Adenovirus receptor (CAR = CXADR) is markedly downregulated in CD45low/CD105+ EP in MDS patients compared to control EP. Correspondingly, the erythroblast cell lines HEL, K562, and KU812 stained negative for CAR. Lentiviral transduction of the full-length CXADR gene into these cells resulted in an increased expression of early erythroid antigens, including CD36, CD71, and glycophorin A. In addition, CXADR-transduction resulted in an increased migration against a serum protein gradient, whereas truncated CXADR variants did not induce expression of erythroid antigens or migration. Furthermore, conditional knock-out of Cxadr in C57BL/6 mice resulted in anemia and erythroid dysplasia. Finally, decreased CAR expression on EP was found to correlate with high-risk MDS and decreased survival. Together, CAR is a functionally relevant marker that is down-regulated on EP in MDS and is of prognostic significance. Decreased CAR expression may contribute to the maturation defect and altered migration of EP and thus their pathologic accumulation in the BM in MDS.
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Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.
2020-07-02 | GSE129691 | GEO
Project description:CD34 positive cells of bone marrow samples from normal and MDS samples were cultured ex vivo into erythroid conditions. We used microarrays to detail the gene expression programm of erythroid cells between normal and pathological (MDS) samples Mononuclear cells from bone marrow samples were selected on the expression of the CD34 membran marker. Then, they were cultured ex vivo during 14 days and total RNA samples were analyzed at day 7, 10 and/or 14 then compared between normal and MDS samples.
2012-02-14 | E-GEOD-34268 | biostudies-arrayexpress
Project description:CD34 positive cells of bone marrow samples from normal and MDS samples were cultured ex vivo into erythroid conditions. We used microarrays to detail the gene expression programm of erythroid cells between normal and pathological (MDS) samples
2012-02-14 | GSE34268 | GEO
Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals that CD18 is a major effector of St3gal1 in activated CD8 T cells. St3gal1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR-T cells with enhanced expression of bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
2023-03-17 | GSE227429 | GEO
Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals that CD18 is a major effector of St3gal1 in activated CD8 T cells. St3gal1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR-T cells with enhanced expression of bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
2023-03-17 | GSE227509 | GEO
Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals that CD18 is a major effector of St3gal1 in activated CD8 T cells. St3gal1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR-T cells with enhanced expression of bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
2023-03-17 | GSE227430 | GEO
Project description:Myelodysplastic Syndromes (MDSs) are a heterogeneous family of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis and frequently leukemia progression. To exlore how MDS develop into leukemia, we performed the transcriptional profiling of lesional cells and normal lymphoid cells from the MDS patients. Bone marrow cells from the MDS patients were sorted into blastic, myeloid, erythroid and lymphoid fractions by flow cytometry and then were profiled transcriptionally by Human Human Genome U133 Plus 2.0 arrays. Differentially expressed genes between lesional cells and lymphoid cells were identified by SAM.
2009-05-28 | E-GEOD-16236 | biostudies-arrayexpress
Project description:KLF2 is a Krüppel-like zinc-finger transcription factor required for blood vessel, lung, T-cell, and erythroid development. KLF2-/- mice die by embryonic day 14.5 (E14.5), due to hemorrhaging and heart failure. Embryonic -like globin gene expression is reduced in KLF2-/- embryos compared to wildtype (WT), and E10.5 erythroid cells exhibit abnormal morphology. Other KLF2 target genes were identified by comparing E9.5 KLF2-/- and WT yolk sac erythroid cells, using laser capture microdissection and microarray assays. One hundred and ninety-six genes exhibited significant differences in expression; eighty-nine of these are downregulated in KLF2-/- compared to WT. Genes involved in cell migration, differentiation and development are over-represented in the KLF2-regulated gene list. Previously identified erythroid-enriched regulatory genes such as reelin, adenylate cyclase 7, cytotoxic T lymphocyte-associated protein 2 alpha, and CD24a antigen are downregulated in KLF2-/- compared to WT. SOX2, a pluripotency factor in ES cells, is also a KLF2 target in embryonic erythroid cells. We investigated whether reelin, which has an established role in neuronal migration and proliferation, has a role in embryonic erythropoiesis. Luciferase reporter assays demonstrated that KLF2 directly transactivates the reelin promoter, but reelin mutant mice have no apparent abnormalities in embryonic erythroid morphology or globin gene expression. Timed-pregnant KLF2+/- females were anesthetized and sacrificed. E9.5 yolk sacs were dissected from the embryo, cryoprotected in 20% sucrose in PBS and frozen in OCT media. A small portion of the embryo tail was used for PCR genotyping. Eight micron KLF2-/- frozen yolk sac sections were obtained and laser capture microdissection (LCM) was used to isolate primitive erythroid precursors. For each biological replicate, 2 to 4 yolk sacs from 2 different litters were used. Total RNA was isolated from 4 different KLF2-/- erythroid samples and hybridized to Affymetrix 430 A 2.0 microarrays
2011-03-02 | E-GEOD-27602 | biostudies-arrayexpress