DOT1L controls NK cell maturation and lineage integrity
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PROVIDER: PRJNA918648 | ENA |
REPOSITORIES: ENA
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Project description:DOT1L controls NK cell maturation and lineage integrity [CUT&TAG]
| PRJNA918655 | ENA
Project description:Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system. In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.
2024-04-30 | GSE222232 | GEO
Project description:In the innate immune system, natural killer (NK) cells represent a highly important subset of cells with utmost importance in the control of transformed cell and tumour inflammation. Previous studies showed that NK cells can convert into ILC1-like cells in a TGF-β-rich tumour microenvironment (TME). In addition, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of the proinflammatory cytokines IFN-γ and TNF in addition to decreased granzyme B production. Here, we identify the histone methyltransferase DOT1L as a critical regulator of NK cell lineage integrity in vitro and in vivo. NK cells from NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) show increased frequencies of ILC1-like cells (CD49b+ CD49a+), and also express more of the ILC1 markers CD200R, TRAIL, while showing reduced expression of Ly49H. We further identify that the increased ILC1-like phenotype is largely independent of TGFβ. Assessment of transcription factor (TF) availability in the absence of DOT1L shows that the Myocyte-specific enhancer factor (MEF)2C is the highest downregulated TF in the absence of DOT1L. CRISPRCas9-mediated deletion of MEF2C ultimately provides evidence that this TF is limiting NK cell plasticity in vivo. Our findings provide evidence for a previously unknown role of DOT1L and MEF2C in NK cell biology for maintaining NK cell lineage integrity and may ultimately result in improved therapies for patients with leukemia or other NK cell-lineage dependent malignancies.
2024-04-30 | GSE222234 | GEO
Project description:DOT1L controls NK cell maturation and lineage integrity [RNA-seq D5]
| PRJNA918658 | ENA
Project description:Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system. In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.
2024-04-30 | GSE222233 | GEO
Project description:DOT1L controls NK cell maturation and lineage integrity [RNA-seq D0 & D2]
| PRJNA918656 | ENA
Project description:Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system. In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.
2024-04-30 | GSE222323 | GEO
Project description:DOT1L controls NK cell activation and lineage integrity [ChIP-seq]
| PRJNA919177 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-30 | GSE222235 | GEO
Project description:We wanted to investigate the effects of Dot1l deletion on gene expression in LSKs and GMPs of C57/BL6 mice Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Lineage negative Sca-1 positive Kit positive (LSK) cells and granulocyte macrophage progenitors (GMPs) were sorted from Dot1 wt/wt x Mx-Cre mice or Dot1l fl/fl x Mx-Cre mice were injected with PIPC. PIPC injection induced biallelic deletion of the Dot1l allele in the Dot1l fl/fl mice but not the Dot1l wt/wt mice. The Dot1l wt/wt LSKs and GMPs were compared to the Dot1l -/- counterparts by RNA extraction and Microarrays.
2014-09-08 | E-GEOD-54498 | biostudies-arrayexpress