Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue–inducer cell and NK cell lineages

Aliahmad, Parinaz; Torre, Brian de la; Kaye, Jonathan

doi:10.1038/ni.1930

Cited by 218 publications

(220 citation statements)

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“…Genes encoding cytokine receptors IL2ra and IL7r, important in NK cell expansion and survival (27,28), were also increased in Ezh2-deficient NKp cells. Moreover, the abundance of mRNAs encoding chemokine receptors (Cxcr3, Ccr7, Xcr1), costimulatory and activating receptors (Slamf7, Tnfrsf9), Toll-like receptors (Tlr3, Tlr8), TFs (Tox, Blimp1) (29), and cytotoxicity-related proteases (Gzma, Gzmb) were also elevated following deletion of Ezh2 (Fig. 4D).…”

Section: Resultsmentioning

confidence: 94%

Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

Yin

Leavenworth

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

124

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Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27 me3 ) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122 + NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies.epigenetic regulation | NKG2D | hematopoietic stem and progenitor cells | histone modification | innate immunity

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Section: Resultsmentioning

confidence: 94%

Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

Yin

Leavenworth

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

124

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“…S6B). Many transcripts associated with Eomes and T-bet activity were also up-regulated, including those encoding molecules associated with NK cell maturation (e.g., Klrg1 and Tox) (23)(24)(25)(26), survival (e.g., Bcl2, Il2rβ, and Il2rγ) (27,28), effector function [e.g., Klrk1 (encoding NKG2D), Prf1 (encoding perforin), Gzmk (encoding granzyme k)] and memory formation (e.g., Cxcr6 and Thy1) (29,30) (Fig. S6B).…”

Section: Molecular Mechanisms For Opn-i-dependent Regulation Of Nk Cellmentioning

confidence: 99%

Intracellular osteopontin regulates homeostasis and function of natural killer cells

Leavenworth

Verbinnen

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i–deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i–deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer.

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“…This gene has been proposed as one of two candidate genes in recurring 8q12.1 deletions that are present in approximately 4% of ALL [32]. TOX, originally shown to play a role in T-cell development, has recently been found to be involved in the development of many cell lineages of the immune system [33]. In Case 16, the 160-kb deletion of 8q12.1 includes the first 5' exon of TOX and does not involve any other genes; therefore, our results further support TOX as a significant candidate gene within these 8q12.1 deletions.…”

Section: Discussionmentioning

confidence: 99%

CGH-based microarray detection of cryptic and novel copy number alterations and balanced translocations in cytogenetically abnormal cases of b-cell all

Schultz¹,

Tsuchiya²,

Furrow³

et al. 2013

Health

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Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with the majority of cases being of precursor B-cell phenoltype. Conventional cytogenetic analysis plays an important role in the diagnosis of B-cell ALL, identifying characteristic chromosomal abnormalities associated with a given prognosis therein facilitating optimized treatment. The more recent introduction of microarray technology to the analysis of B-cell ALL has afforded both higher resolution for the detection of known abnormalities and an ability to identify novel copy number abnormalities (CNAs) with potential clinical relevance. In the current study, microarray analysis was performed on 20 cytogenetically abnormal B-cell ALL cases (10 pediatric and 10 adult), while a novel microarray-based balancedtranslocation detection methodology (translocation CGH or tCGH) was applied to that subset of cases with a known or suspected recurrent balanced translocation. Standard microarray analysis identified that CNAs was not detected by previous conventional cytogenetics in 75% (15/20) cases. tCGH identified 9/9 (100%) balanced translocations defining BCR/ABL1 (x4), ETV6/RUNX1 (x3), and MLL/AFF1 (x2) breakpoints with high resolution. The results illustrate the improved molecular detail afforded by these technologies and a comparison of translocation breakpoints, CNAs and patient age offers new insights into tumor biology with potential prognostic significance.

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Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue–inducer cell and NK cell lineages

Cited by 218 publications

References 50 publications

Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

Intracellular osteopontin regulates homeostasis and function of natural killer cells

CGH-based microarray detection of cryptic and novel copy number alterations and balanced translocations in cytogenetically abnormal cases of b-cell all

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