An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response

Adams, Brian D.; Guo, Shangqin; Bai, Hao; Guo, Yanwen; Megyola, Cynthia M.; Cheng, Jijun; Heydari, Kartoosh; Xiao, Changchun; Reddy, E. Premkumar; Lü, Jun

doi:10.1016/j.celrep.2012.09.014

Cited by 42 publications

(42 citation statements)

References 36 publications

(54 reference statements)

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“…miR-150-5p is evolutionarily conserved, and previous studies have shown it as a key regulator of the transcription factor c-Myb, a regulator of hematopoiesis in multiple lineages [36,37]. An in vivo gain of function screen has identified miR-150-5p as an inhibitor of hematopoietic recovery upon marrow injury induced by the chemotherapeutic agent 5-flurouracil [38], where depletion of miR-150-5p resulted in enhanced hematopoietic recovery [38]. Also, studies using miR-150 knockout mice shows its effect on inhibition of inflammation and apoptotic response after myocardial infarction induced acute kidney injury [39].…”

Section: Discussionmentioning

confidence: 99%

Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

et al. 2016

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Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be utilized to screen for tissue toxicity in patients who receive myeloablative and therapeutic radiation.

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Section: Discussionmentioning

confidence: 99%

Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

et al. 2016

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“…At the same time, management of hematopoietic injury is a major clinical question in both chemo and radiation based cancer therapies. Recent studies show that miRNA-150 control hematopoiesis [29], [30], [31] and their dose and time dependent changes should provide readouts for the conditioning as well as hematopoietic injury response [31]. Recent genetic studies have shown that overexpression of miRNA-150 results in a slow recovery rate after 5-fluorouracil induced injury in a mouse model for bone marrow transplant [30].…”

Section: Discussionmentioning

confidence: 99%

Identification of Sensitive Serum microRNA Biomarkers for Radiation Biodosimetry

et al. 2013

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Exposure to ionizing radiation through environmental, occupational or a nuclear reactor accident such as the recent Fukushima Daiichi incident often results in major consequences to human health. The injury caused by radiation can manifest as acute radiation syndromes within weeks in organs with proliferating cells such as hematopoietic and gastrointestinal systems. Cancers, fibrosis and degenerative diseases are also reported in organs with differentiated cells, months or years later. Studies conducted on atom bomb survivors, nuclear reactor workers and animal models have shown a direct correlation of these effects with the absorbed dose. Physical dosimeters and the available radio-responsive biologics in body fluids, whose responses are rather indirect, have limitations to accurately evaluate the extent of post exposure damage. We have used an amplification-free, hybridization based quantitative assay utilizing the nCounter multiplex platform developed by nanoString Technologies to compare the levels of over 600 miRNAs in serum from mice irradiated at a range of 1 to 12 Gy at 24 and 48 hr time points. Development of a novel normalization strategy using multiple spike-in oligonucleotides allowed accurate measurement of radiation dose and time dependent changes in serum miRNAs. The response of several evolutionarily conserved miRNAs abundant in serum, were found to be robust and sensitive in the dose range relevant for medical triage and in patients who receive total body radiation as preparative regimen for bone marrow transplantation. Notably, miRNA-150, abundant in lymphocytes, exhibited a dose and time dependent decrease in serum, which we propose as a sensitive marker indicative of lymphocyte depletion and bone marrow damage. Our study has identified several markers useful for evaluation of an individual’s response by minimally invasive methods, relevant to triage in case of a radiation accident and evaluation of toxicity and response during and after therapeutic radiation.

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“…Assessment of hematopoietic phenotypes were performed as previously described (Guo et al, 2012; Adams et al, 2012; Guo et al, 2010). Myeloid bias index was used to quantify biased differentiation into myeloid lineages, which was calculated by (%GFP+Mac1+)/(%GFP+Mac1−)/((%GFP−Mac1+)/(%GFP−Mac1−)).To examine monocytic differentiation bias, Mac1+ cells from GFP+ fraction (transduced) were gated before examining Ly6C and Ly6G distribution.…”

Section: Methodsmentioning

confidence: 99%

An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

et al. 2013

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Summary The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation and such TET2-targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3′UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs in vivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas co-expression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wildtype acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC, and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.

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An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response

Cited by 42 publications

References 36 publications

Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

Identification of Sensitive Serum microRNA Biomarkers for Radiation Biodosimetry

An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

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