Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity

Giambra, Vincenzo; Gusscott, Samuel; Gracias, Deanne; Song, Raymond; Lam, Sonya H.L.; Panelli, Patrizio; Tyshchenko, Kateryna; Jenkins, Catherine E.; Hoofd, Catherine; Lorzadeh, Alireza; Carles, Annaïck; Hirst, Martin; Eaves, Connie J.; Weng, Andrew P.

doi:10.1016/j.stem.2018.08.018

Cited by 18 publications

(12 citation statements)

References 78 publications

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“…KEGG pathway analysis of the differentially expressed genes highlighted the “transcriptional misregulation in cancer” pathway as the most extensively affected (Fig. 5d, e ); Several genes in this pathway, such as Cebpe 46 , Erg 47 , Igf1 48 , Mmp9 49 , Mpo 50 , Pax5 51 , Prom1 52 are involved in leukemia. These data indicate an ORP4L-dependent gene reprogramming upon the T-cells deterioration.…”

Section: Resultsmentioning

confidence: 99%

An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

et al. 2022

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Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P3] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis.

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Section: Resultsmentioning

confidence: 99%

An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

et al. 2022

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“…An empty vector, expressing only the sfGFP was also included as a control. Cell transfection was achieved using Polyethylenimine Linear, MW25000, Transfection Grade (PEI 25K) (Polysciences, Inc., Warrington, PA, USA) as described previously [ 27 ]. After transfection, HEK-293T cells were in vitro expanded for 2 days and subsequently assessed for GFP and Strep-Tag II expression by flow cytometry using an anti-Strep-tag II primary antibody (cat.…”

Section: Methodsmentioning

confidence: 99%

COVID-19 Specific Immune Markers Revealed by Single Cell Phenotypic Profiling

et al. 2021

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COVID-19 is a viral infection, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and characterized by a complex inflammatory process and clinical immunophenotypes. Nowadays, several alterations of immune response within the respiratory tracts as well as at the level of the peripheral blood have been well documented. Nonetheless, their effects on COVID-19-related cell heterogeneity and disease progression are less defined. Here, we performed a single-cell RNA sequencing of about 400 transcripts relevant to immune cell function including surface markers, in mononuclear cells (PBMCs) from the peripheral blood of 50 subjects, infected with SARS-CoV-2 at the diagnosis and 27 healthy blood donors as control. We found that patients with COVID-19 exhibited an increase in COVID-specific surface markers in different subsets of immune cell composition. Interestingly, the expression of cell receptors, such as IFNGR1 and CXCR4, was reduced in response to the viral infection and associated with the inhibition of the related signaling pathways and immune functions. These results highlight novel immunoreceptors, selectively expressed in COVID-19 patients, which affect the immune functionality and are correlated with clinical outcomes.

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“…An empty vector, expressing only the sfGFP, was used as control. HEK-293T cells were transiently transfected using Polyethylenimine Linear, MW25000, Transfection Grade (PEI 25K) (Polysciences, Inc., Warrington, PA, USA), as described previously [ 28 ]. After transfection, HEK-293T cells were cultured for 2 days and subsequently assessed for GFP expression by flow cytometry before protein purification.…”

Section: Methodsmentioning

confidence: 99%

Associations between Allelic Variants of the Human IgH 3′ Regulatory Region 1 and the Immune Response to BNT162b2 mRNA Vaccine

et al. 2021

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The escalation of Coronavirus disease 2019 (COVID-19) has required the development of safe and effective vaccines against the severe acute respiratory syndrome coronavirus 2-associated (SARS-CoV-2), which is the causative agent of the disease. Here, we determined the levels of antibodies, antigen-specific B cells, against a recombinant GFP-tagged SARS-CoV-2 spike (S) protein and total T and NK cell subsets in subjects up to 20 days after the injection of the BNT162b2 (Pfizer–BioNTech) vaccine using a combined approach of serological and flow cytometry analyses. In former COVID-19 patients and highly responsive individuals, a significant increase of antibody production was detected, simultaneous with an expansion of antigen-specific B cell response and the total number of NK-T cells. Additionally, through a genetic screening of a specific polymorphic region internal to the 3’ regulatory region 1 (3’RR1) of human immunoglobulin constant-gene (IgH) locus, we identified different single-nucleotide polymorphic (SNP) variants associated with either highly or lowly responsive subjects. Taken together, these results suggest that favorable genetic backgrounds and immune profiles support the progression of an effective response to BNT162b2 vaccination.

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Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity

Cited by 18 publications

References 78 publications

An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

COVID-19 Specific Immune Markers Revealed by Single Cell Phenotypic Profiling

Associations between Allelic Variants of the Human IgH 3′ Regulatory Region 1 and the Immune Response to BNT162b2 mRNA Vaccine

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