MicroRNA-29b mediates altered innate immune development in acute leukemia

Mundy-Bosse, Bethany L.; Scoville, Steven D.; Chen, Li; McConnell, Kathleen; Mao, Hsiaoyin; Ahmed, Elshafa H.; Zorko, Nicholas; Harvey, Sophia; Cole, Jordan P.; Zhang, Xiaoli; Costinean, Stefan; Croce, Carlo M.; Larkin, Karilyn; Byrd, John C.; Vasu, Sumithira; Blum, William; Yu, Jianhua; Freud, Aharon G.; Caligiuri, Michael A.

doi:10.1172/jci85413

Cited by 54 publications

(87 citation statements)

References 59 publications

(82 reference statements)

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“…Micro-RNA29b, a negative regulator of both T-bet and Eomes (Fig. 4) was found to be upregulated in NK cells from leukemic mice and patients, which could contribute to this phenomenon [131]. The GSK3 kinase may also control T-bet expression in NK cells.…”

Section: Other Pathwaysmentioning

confidence: 96%

T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1

et al. 2018

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T-bet and Eomes are T-box transcription factors that drive the differentiation and function of cytotoxic lymphocytes such as NK cells. Their DNA-binding domains are highly similar, suggesting redundant transcriptional activity. However, while these transcription factors have different patterns of expression, the phenotype of loss-of-function mouse models suggests that they play distinct roles in the development of NK cells and other innate lymphoid cells (ILCs). Recent technological advances using reporter mice and conditional knockouts were fundamental in defining the regulation and function of these factors at steady state and during pathological conditions such as various types of cancer or infection. Here, we review these recent developments, focusing on NK cells as prototypical cytotoxic lymphocytes and their development, and also discuss parallels between NK cells and T cells. We also examine the role of T-bet and Eomes in human NK cells and ILC1s. Considering divergent findings on mouse and human ILC1s, we propose that NK cells are defined by coexpression of T-bet and Eomes, while ILC1s express only one of these factors, either T-bet or Eomes, depending on the tissue or the species.

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Section: Other Pathwaysmentioning

confidence: 96%

T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1

et al. 2018

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“…In this model, miR‐29b specifically down‐regulated TEBT and EOMES expression, inhibiting maturation of NK cells in this mouse model. NK cells play an important role in the death of tumor cells; interestingly, a high level of miR‐29b induced the depletion of NK cells, indicating a potential mechanism of microRNA‐mediated immune‐escape in cancer …”

Section: Gene Regulation By Microrna In Nk Cellsmentioning

confidence: 99%

Noncoding RNA in NK cells

Yang

Shen

Feng

et al. 2018

Journal of Leukocyte Biology

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Noncoding RNAs (ncRNA) are important regulators that modulate cell proliferation, apoptosis, the cell cycle, and DNA methylation. NK cells mediate the immune response via the secretion of various cytokines and are important innate immune cells in the human immune system. Recent studies have found that ncRNA plays an important role in NK cell development and function. With recent advances in bioinformatics and next-generation sequencing, novel ncRNAs have been identified, allowing us to more fully appreciate its functions in NK cell biology. In this review, we summarize and discuss the latest studies on the functions and regulatory mechanisms of long noncoding RNA (lncRNA) and microRNA in NK cells from the viewpoint of epigenetic mechanisms to help us clearly understand ncRNA in NK cells. K E Y W O R D Scytokines, gene regulation mechanism, immune response, lncRNA, microRNA, NK cell the roles of ncRNA, mainly lncRNA and microRNA, in NK cell development and function. We also summarize the latest studies and discuss the potential regulation of NK cell biologic processes by lncRNA and microRNA.

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“…The disappearance of NK cells from the bone marrow of MYC ON mice (Supplementary 215 Figure 7) suggested that MYC-driven lymphomagenesis might abrogate the replenishment of 216 mature CD3 -NKp46 + NK cells in the periphery possibly by blocking early NK cell development 217 [24][25][26][27] . We tested this possibility by comparing the absolute counts of NK cell precursors (NKP, 218 CD122 + NKp46 -, Figure 3a), and the more differentiated CD122 + NKp46 + iNK (immature NK, 219 (Figure 3c).…”

Section: Maturation Of Nk Cells Is Arrested During Myc-driven Lymphommentioning

confidence: 99%

“…Hence, we conclude MYC-driven lymphomas evade NK cell-mediated 423 immune surveillance by blocking NK cell maturation, and infer that inhibiting MYC is essential 424 for reversing this developmental blockade and eliciting an NK cell-mediated response against 425 "MYC-addicted" tumors. Arrest in NK cell maturation has been demonstrated to be a critical 426 mechanism of immune escape in cancers 26,27 . Our findings demonstrate that the overexpression Figures 10, 15).…”

Section: Nk Cells In Myc-driven Lymphoma Initiation and Recurrence Pmentioning

confidence: 99%

MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

Swaminathan

Heftdal

Liefwalker

et al. 2018

Preprint

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34The MYC oncogene drives T and B lymphoid malignancies, including Burkitt's lymphoma (BL) 35and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction 36 in natural killer (NK) cell-mediated surveillance in SRα-tTA/Tet-O-MYC ON mice bearing MYC-37driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic 38 MYC releases the brakes on NK maturation restoring NK homeostasis. Lymphoma-intrinsic 39 MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I 40 Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by 41 rescuing NK cell maturation. In MYC-driven BL patients, low expression of both STAT1 and 42 STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable 43 clinical outcomes. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma 44 growth and recurrence post MYC inactivation. Our studies thus provide a rationale for 45 developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future. 46Oncogene addiction is the phenomenon where a cancer becomes causally dependent on a single 47 'driver' oncogene for the maintenance of its proliferation and survival 1,2 . Inhibition of the driver 48 oncogene forms the basis of oncogene targeted therapy 1-3 . Hence, a potential Achilles' heel of 49 human malignancies lies in their addiction to oncogenes such as MYC, RAS and BCR-ABL1 4,5 . 50Targeted therapy has been successful against BCR-ABL1 (Philadelphia/Ph + )-induced leukemia 51 6,7 , while therapies that successfully target MYC or RAS remain to be developed. 52In order to develop targeted therapies for MYC-driven cancers, it is vital to understand 53 whether MYC regulates both cell autonomous and non-autonomous processes, including host 54 immunity. Oncogene addiction was previously assumed to be cell autonomous and immune-55 independent 8 . Many recent studies illustrate that MYC and other oncogenes alone or 56 cooperatively may regulate the tumor microenvironment and host immune responses in multiple 57 tumor types 9-16 . In particular, two reports highlighted that oncogenes may cooperate to more 58 globally regulate the host immune system 12,16 . 59We have used a particularly tractable approach for studying the role of the host immune 60 system during MYC-driven tumorigenesis through tetracycline (tet)-system regulated transgenic 61 mouse models of cancer. Our inducible mouse models enable us to study how MYC inactivation 62 elicits tumor regression through both cancer-intrinsic and cancer-extrinsic host immune-63 dependent mechanisms 11,13 . CD4 + T cells appear to be essential for the sustained regression of 64 cancers upon MYC inactivation 11,13 . However, the changes in immune landscape during primary 65 MYC-induced tumorigenesis in these models remain to be delineated. 66Our goal was to delineate the global immunological changes resulting from primary overt 67 MYC-driven lymphomagenesis, to identify...

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MicroRNA-29b mediates altered innate immune development in acute leukemia

Cited by 54 publications

References 59 publications

T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1

T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1

Noncoding RNA in NK cells

MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

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