Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA394158 | ENA |
REPOSITORIES: ENA
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Project description:We determined the global expression profile of DNAM-1+ and DNAM-1- NK cell purified by flow cytometry from 6 different groups of C57BL/6 WT mice. Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1- NK cells. DNAM-1+ NK cells have enhanced Interleukin 15 signaling, proliferate vigorously and produce high levels of inflammatory cytokines. By contrast, DNAM-1- NK cells that differentiate from DNAM-1+ NK cells, have greater expression of NK cell receptor related genes and are higher producers of chemokines. Together our findings highlight the existence of two distinct effector programs in innate lymphocytes controlled through DNAM-1 expression. NK1.1+NKp46+CD3- DNAM-1+ and DNAM-1- NK cell were purified by flow cytometry from 6 different groups of C57BL/6 WT mice and total RNA were extracted
2015-02-26 | E-GEOD-66281 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. 5 normal AML cells were compared with 8 NK deficient AML cells.
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Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. Gene expression analysis were performed on CD56bright and CD56dim NK cells sorted from patients with impaired or normal CD56bright NK cells (n=2 for each patients? group) and from 3 HC
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Project description:We determined the global expression profile of DNAM-1+ and DNAM-1- NK cell purified by flow cytometry from 6 different groups of C57BL/6 WT mice. Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1- NK cells. DNAM-1+ NK cells have enhanced Interleukin 15 signaling, proliferate vigorously and produce high levels of inflammatory cytokines. By contrast, DNAM-1- NK cells that differentiate from DNAM-1+ NK cells, have greater expression of NK cell receptor related genes and are higher producers of chemokines. Together our findings highlight the existence of two distinct effector programs in innate lymphocytes controlled through DNAM-1 expression.
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Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.
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Project description:The relative importance of T/B lymphocytes and NK cells during acute myeloid leukemia (AML) progression has been unclear. In this study, we compared gene expression profiles of mouse AML cells expressing MLL-AF9 collected from immunologically normal wild-type (WT) C57BL/6 mice, Rag2-/- mice lacking mature T and B cells, and NSG mice lacking T, B and NK cells.
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Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.
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