Identification of novel microRNA signatures linked to acquired aplastic anemia

Hosokawa, Kohei; Muranski, Pawel; Feng, Xingmin; Keyvanfar, Keyvan; Townsley, Danielle M.; Dumitriu, Bogdan; Chen, Jichun; Taylor, James G.; Hourigan, Christopher S.; Barrett, A. John; Young, Neal S.

doi:10.3324/haematol.2015.126128

Cited by 31 publications

(41 citation statements)

References 57 publications

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“…Nonetheless, our data strongly suggest that aberrant miRNA expression was disease-related, especially as the restoration of miRNA levels was observed after IST. In our recent work, we identified concurrent downregulation of 4 miRNAs (miR-126-3p, miR-145-5p, miR-199a-5p, and miR-223-3p) in both CD4 + and CD8 + T cells from AA patients, 14 but dysregulation of the 4 miRNAs was not observed in AA plasma samples in the study herein. Previous reports in autoimmune diseases 12,20,[52][53][54][55][56][57][58][59] and cancers, [60][61][62][63] have also demonstrated discrepancies of expression profiles between cellular and circulating miRNAs.…”

Section: Discussionmentioning

confidence: 79%

“…Indeed, miRNA expression profiles are cell-type specific. Of note, regardless of discrepancies between cellular and circulating miRNA profiles, we could observe some common miRNA signatures in both AA and MG, such as decreased miR-145-5p in T cells 14,64 and increased miR-150-5p in plasma specimens. 21 In conclusion, we demonstrate that expression levels of 3 dysregulated miRNAs in AA plasma associate with clinical parameters and normalize after IST, suggesting their use as potential biomarkers in AA.…”

Section: Discussionmentioning

confidence: 92%

“…13 We have recently reported that downregulation of miR-126-3p and miR-145-5p promotes CD4 + and CD8 + T-cell activation by increasing MYC and PIK3R2 expression levels in AA patients. 14 MiRNAs can also be detected outside the cell. Extracellular miRNAs are cell-free circulating molecules residing in microvesicles, exosomes, and microparticles.…”

Section: Introductionmentioning

confidence: 99%

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A plasma microRNA signature as a biomarker for acquired aplastic anemia

et al. 2016

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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A plasma microRNA signature as a biomarker for acquired aplastic anemia

et al. 2016

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“…23 Augmented expression of granzymes B and C and perforin in DGKζ -/mouse BM denotes an increase in cytotoxic T cells (CTL) similar to that described in AA patients. 24 Activated T lymphocytes cause BM destruction in AA; 25 DGKζ -/mice showed reduced BM cellularity ( Figure 1D). Analysis of the TER-119 + erythroid lineage populations did not show differences between DGKζ -/and WT mice ( Figure 1E).…”

Section: Resultsmentioning

confidence: 98%

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado¹,

Andrada

Liébana³

et al. 2020

Preprint

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Key points• DGKζ-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFNγ and lytic enzymes.• DGKζ loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. Visual abstractAbstract Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase ζ (DGKζ) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKCθ/NFκB pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGKζ -/mice showed increased numbers of activated T cells in BM, together with a significant increase in IFNγ as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGKζ -/mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGKζ expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGKζ expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGKζ deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development.

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“…Our results provide the first evidence that miR-126* promotes pGC apoptosis. Hosokawa et al (2015) demonstrated that miR-126* knockdown promotes proliferation and increases interferon-γ and granzyme B production in CD4+ and CD8+ T cells. In addition, overexpression of miR-126* significantly inhibits cell proliferation in thyroid cancer (Xiong et al 2015) and breast cancer cells (Rohde et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

Du¹,

Pan²,

Li³

2016

Reproduction

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Androgen, which acts via the androgen receptor (AR), plays crucial roles in mammalian ovarian function. Recent studies showed that androgen/AR signaling regulates follicle-stimulating hormone receptor (FSHR) expression in follicles; however, the detailed mechanism underlying this regulation remained unknown. Here, we demonstrate that AR and miR-126* cooperate to inhibit FSHR expression and function in pig follicular granulosa cells (pGCs). In pGCs, overexpression of AR decreased, whereas knockdown increased, FSHR mRNA and protein expression; however, neither manipulation affected FSHR promoter activity. Using a dualluciferase reporter assay, we found that the FSHR gene is a direct target of miR-126*, which inhibits FSHR expression and increases the rate of AR-induced apoptosis in pGCs. Collectively, our data show for the first time that the AR/miR-126* axis exerts synergetic effects in the regulation of FSHR expression and apoptosis in pGCs. Our findings thus define a novel pathway, AR/miR-126*/FSHR, that regulates mammalian GC functions.Reproduction (2016) 152 161-169

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Identification of novel microRNA signatures linked to acquired aplastic anemia

Cited by 31 publications

References 57 publications

A plasma microRNA signature as a biomarker for acquired aplastic anemia

A plasma microRNA signature as a biomarker for acquired aplastic anemia

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

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