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MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation (c-Myb overexpression)

ABSTRACT: NK cells develop in the bone marrow and complete their maturation in peripheral organs, but the molecular events controlling maturation are incompletely understood. Utilizing an NK cell-specific miR-15/16 deficient genetic model (15aKO), we identified a critical role for miR-15/16 family microRNAs in the normal maturation of NK cells in vivo, with a specific reduction in mature CD11b+CD27- NK cells in multiple tissues. The mechanism responsible was a block in differentiation, since accelerated NK cell death was not evident, and earlier intermediates of NK cell maturation were expanded. Further, we identified Myb as a direct target of miR-15/16 in NK cells, with Myb expression increased in immature 15aKO NK cells. Following adoptive transfer, immature 15aKO NK cells exhibited defective maturation, which was rescued by ectopic miR-15/16 expression or Myb knockdown. Moreover, Myb overexpression resulted in defective NK cell maturation. Thus, miR-15/16 regulation of Myb controls the normal NK cell maturation program.

ORGANISM(S): Mus musculus

PROVIDER: GSE58268 | GEO | 2015/09/03

SECONDARY ACCESSION(S): PRJNA251855

REPOSITORIES: GEO

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MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation (c-Myb overexpression)

Project description:NK cells develop in the bone marrow and complete their maturation in peripheral organs, but the molecular events controlling maturation are incompletely understood. Utilizing an NK cell-specific miR-15/16 deficient genetic model (15aKO), we identified a critical role for miR-15/16 family microRNAs in the normal maturation of NK cells in vivo, with a specific reduction in mature CD11b+CD27- NK cells in multiple tissues. The mechanism responsible was a block in differentiation, since accelerated NK cell death was not evident, and earlier intermediates of NK cell maturation were expanded. Further, we identified Myb as a direct target of miR-15/16 in NK cells, with Myb expression increased in immature 15aKO NK cells. Following adoptive transfer, immature 15aKO NK cells exhibited defective maturation, which was rescued by ectopic miR-15/16 expression or Myb knockdown. Moreover, Myb overexpression resulted in defective NK cell maturation. Thus, miR-15/16 regulation of Myb controls the normal NK cell maturation program. KY-1 and KY-2 cell lines overexpressing c-Myb

2015-09-03 | E-GEOD-58268 | biostudies-arrayexpress

MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation

2015-09-03 | GSE55033 | GEO

MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation

2015-09-03 | E-GEOD-55033 | biostudies-arrayexpress

Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells

Project description:Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a-Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8+ T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases. These findings underscore the importance of STAT5 tetramers in maintaining NK cell homeostasis. Moreover, defective STAT5 tetramer formation could represent a cause of NK cell immunodeficiency, and interrupting STAT5 tetramer formation might serve to control NK leukaemia.

2017-09-19 | GSE101470 | GEO

Defective Drosha Processing Contributes to Downregulation of MiR-15/-16 in Chronic Lymphocytic Leukemia.

Project description:MIR15A and MIR16-1, located in chromosomal band 13q14, are tumor suppressor miRNAs often deleted and downregulated in chronic lymphocytic leukemia (CLL). This downregulation is not only due to loss of 13q, as it occurs also in 13q+/+ CLL patients. We found that a subgroup of CLL patients has a dysregulation of miR-15 /-16 processing intermediates due to defective processing by Drosha. These patients have reduced levels of miR-15a, miR-16 and miR-15b (another member of the miR-15 family), but not of most other miRNAs. Thus, we show that modulation of miRNA maturation leads to specific downregulation of a family of tumor suppressor miRNAs in leukemic cells.

2011-12-31 | GSE30927 | GEO

Defective Drosha Processing Contributes to Downregulation of MiR-15/-16 in Chronic Lymphocytic Leukemia.

2011-12-31 | E-GEOD-30927 | biostudies-arrayexpress

MYB silencing in CD14-myeloblasts

2010-07-14 | GSE21943 | GEO

MYB silencing in CD34+ progenitor cells

Project description:The c-Myb transcription factor is highly expressed in immature hematopoietic cells and down-regulated during differentiation. To define the role of c-Myb in human hematopoietic lineage commitment, we studied the effects of its silencing during the commitment of human CD34+ Hematopoietic stem/progenitor cells. In CD34+ cells c-Myb silencing determined a cell cycle arrest in G0/G1 phase which strongly decreased the clonogenic efficiency, togheter with a reduction of erythroid colonies coupled with an increase of the macrophage and megakaryocyte ones. Moreover, morphological and flow cytometry data supported the preferential macrophage and megakaryocyte differentiation of c-Myb-silenced CD34+ cells. Taken together our data indicate that c-Myb is essential for the commitment along the erythroid and granulocyte lineages but not for the macrophage and megakaryocyte differentiation. Gene expression profiling of c-Myb-silenced CD34+ cells identified some potential c-Myb targets which can account for these effects, to study by Chromatin Immunoprecipitation and Luciferase Reporter Assay.

2010-07-14 | GSE13110 | GEO

MYB silencing in CD14-myeloblasts

Project description:The c-Myb transcription factor is highly expressed in immature hematopoietic cells and down-regulated during differentiation. To define the role of c-Myb during the terminal differentiation of hematopoietic precursors, we studied the effects of its silencing in human primary CD14-myeloblasts, which maintain a granulo-monocyte differentiation bipotentiality. c-Myb-silenced myeloblasts were blocked in the G1 phase of the cell cycle at 24 hours post-nucleofection and subsequently were forced towards macrophage differentiation, as demonstrated by immunophenotypic and morphological analysis. Indeed, c-Myb-silenced CD14- cells differentiate to macrophage even after the treatment with ATRA 10-6 M, demonstrating that the c-Myb knockdown strongly impairs the ability of myeloblasts to differentiate to granulocytes. Gene expression profiling of c-Myb-silenced CD14- cells identified some potential c-Myb targets that can account for these effects. To maximize siRNA transfection efficiency, we utilized the NucleofectorTM technology (Amaxa). CD14- cells were transfected with a mixture of 3 siRNAs targeting c-Myb mRNA, with a non-targeting siRNA as a negative control (NegCTR) and without siRNA (MOCK). c-Myb siRNAs were transfected at days 1 to 3 after the CD14- myeloblasts purification based on the observation that this timing represented a phase of phisiological increase in c-Myb expression in myeloblasts. Western Blot analysis at 24 hours post-nucleofection demonstrated the c-Myb protein knockdown in MYBsiRNA CD14- cells as compared with control samples (MOCK, NegCTR).

2010-07-14 | E-GEOD-21943 | biostudies-arrayexpress

MYB silencing in CD34+ progenitor cells

2010-07-14 | E-GEOD-13110 | biostudies-arrayexpress

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