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IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia

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Frontiers of Medicine 2022年第3期16卷 403-415页

作者： Xiao Huang Tingting Ma Yongmei Zhu Bo Jiao Shanhe Yu Kankan Wang Jian-Qing Mi Ruibao Ren Shanghai Institute of Hematology State Key Laboratory for Medical GenomicsCollaborative Innovation Center of HematologyNational Research Center for translational Medicine(Shanghai)Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge.We have previously shown that interferon regulatory factor-8(IRF8)and IRF4 serve as tumor suppressors in myeloid cells.In this study,we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs.Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis(MF)and secondary AML(sAML)transformed from MPNs versus essential thrombocythemia(ET).Negative correlations between the JAK2V617F allele burden and the expression of IRF8(P<0.05)and IRF4(P<0.001)and between white blood cell(WBC)count and IRF4 expression(P<0.05)were found in ET patients.IRF8 expression was negatively correlated with the JAK2V617F allele burden(P<0.05)in polycythemia vera patients.Complete response(CR),partial response(PR),and no response(NR)were observed in 67.5%,10%,and 22.5%of ET patients treated with hydroxyurea(HU),respectively,in 12 months.At 3 months,patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups.In the 12-month therapy period,low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count.Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype,which may serve as biomarkers for the response to HU in ET.

关键词： myeloproliferative neoplasms IRF4 IRF8 hydroxyurea essential thrombocythemia

Zfyve16 regulates the proliferation of β-lymphoid cells

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Frontiers of Medicine 2018年第5期12卷 559-565页

作者： Xuemei Zhao Donghe Li Qingsong Qiu Bo Jiao Ruihong Zhang Ping Liu Ruibao Ren State Key Laboratory for Medical Genomics Shanghai Institute of Hematology Collaborative Innovation Center of HematologyCollaborative Innovation Center of System Biology Ruo'in Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai200025 China Department of Biology Brandeis University Waltham MA 02454 USA

Zfyve16 (a.k.a. endofin or endosome-associated FYVE-domain protein), a member of the FYVE-domain protein family, is involved in endosomal trafficking and in TGF-β, BMP, and EGFR signaling. The FYVE protein SARA regulates the TGF-β signaling pathway by recruiting Smad2/3 and accelerating their phosphorylation, thereby altering their susceptibility to TGF-β-mediated T cell suppression. Zfyve16 binds to Smad4 and their binding affects the formation of Smad2/3-Smad4 complex in TGF-β signaling. However, the in vivo function of Zfyve16 remains unknown. In this study, we generated a Zfyve16 knockout mouse strain (Zfyve16KO) and examined its hematopoietic phenotypes and hematopoietic reconstruction ability. The proportion of T cells in the peripheral blood of Zfyve16KO mice increases compared with that in wild-type mice. This finding is consistent with the role of Zfyve16 in facilitating TGF-β signaling. Unpredictably, B cell proliferation is inhibited in Zfyve16KO mice. The proliferation potential of Zfyve16KO B-lymphoid cells also significantly decreases in vitro. These results suggest that Zfyve16 inhibits the proliferation of T cells, possibly through the TGF-β signaling, but upregulates the proliferation of B-lymphoid cells.

关键词： Zfyve16 endofin hematopoiesis TGF-β lymphocytes

DDB1-and CUL4-associated factor 8 plays a critical role in spermatogenesis

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Frontiers of Medicine 2021年第2期15卷 302-312页

作者： Xiuli Zhang Zhizhou Xia Xingyu Lv Donghe Li Mingzhu Liu Ruihong Zhang Tong Ji Ping Liu Ruibao Ren Shanghai Institute of Hematology State Key Laboratory for Medical GenomicsNational Research Center for Translational Medicine at ShanghaiCollaborative Innovation Center of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Key Laboratory of Laparoscopic Technology of Zhejiang Province Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310058China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310058China

Cullin-RING E3 ubiquitin ligase(CRL)-4 is a member of the large CRL family in eukaryotes.It plays important roles in a wide range of cellular processes,organismal development,and physiological and pathological conditions.DDB1-and CUL4-associated factor 8(DCAF8)is a WD40 repeat-containing protein,which serves as a substrate receptor for CRL4.The physiological role of DCAF8 is unknown.In this study,we constructed Dcaf8 knockout mice.Homozygous mice were viable with no noticeable abnormalities.However,the fertility of Dcaf8-deficient male mice was markedly impaired,consistent with the high expression of DCAF8 in adult mouse testis.Sperm movement characteristics,including progressive motility,path velocity,progressive velocity,and track speed,were significantly lower in Dcaf8 knockout mice than in wild-type(WT)mice.However,the total motility was similar between WT and Dcaf8 knockout sperm.More than 40%of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation.The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm.In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced.The results demonstrated that DCAF8 plays a critical role in spermatogenesis,and DCAF8 is a key component of CRL4 function in the reproductive system.

关键词： Dcaf8 male infertility spermatogenesis

Targeting the RAS signaling network in cancer

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Targeting the RAS signaling network in cancer

Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

细胞—生命的基础——中国细胞生物学学会2013年全国学...

作者： Ruibao Ren Shanghai Institute of Hematology Shanghai Jiao Tong University School of Medicine

RAS proteins are small GTPases that act as molecular switches,transducing signals from many activated receptors that regulate cell proliferation,survival,and differentiation.Hyperactivation of RAS,either by oncogenic mutations of RAS genes or by mutations of genes that regulate the RAS activity,is common in human cancers.Since the enzymatic activity of RAS is used to turn itself off and

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Frontiers of Medicine 2022年第5期16卷 784-798页

作者： Yan Zhang Baoyuan Zhang Yongyun Li Yuting Dai Jiaoyang Li Donghe Li Zhizhou Xia Jianming Zhang Ping Liu Ming Chen Bo Jiao Ruibao Ren Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiCollaborative Innovation Center of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghai 200001China Department of Biology Brandeis UniversityWalthamMA 02454USA

More than 85%of patients with uveal melanoma(UM)carry a GNAQ or GNA11 mutation at a hotspot codon(Q209)that encodes G proteinαsubunit q/11 polypeptides(Gα_(q/11)).GNAQ/11 relies on palmitoylation for membrane association and signal transduction.Despite the palmitoylation of GNAQ/11 was discovered long before,its implication in UM remains unclear.Here,results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells.Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^(Q209L)-induced malignant transformation in NIH3T3 cells.Importantly,the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells,which are much more dependent on Gα_(q/11) signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations.Furthermore,the palmitoylation inhibitor,2-bromopalmitate,also specifically disrupted Gα_(q/11) downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor,ABT-199,in vitro.The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.

关键词： uveal melanoma mutant GNAQ/11 palmitoylation BCL2 combination target therapy

Comparison of UV-based advanced oxidation processes for the removal of different fractions of NOM from drinking water

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Journal of Environmental Sciences 2023年第4期126卷 387-395页

作者： Zhenxing Yao Mingquan Wang ruibao Jia Qinghua Zhao Li Liu Shaohua Sun Shandong Province City Water Supply and Drainage Water Quality Monitoring Center Jinan 250101China

This study examined the effectiveness for degradation of hydrophobic (HPO),transphilic(TPI) and hydrophilic (HPI) fractions of natural organic matter (NOM) during UV/H_(2)O_(2),UV/TiO_(2)and UV/K2S2O8(UV/PS) advanced oxidation processes (AOPs).The changing characteristics of NOM were evaluated by dissolved organic carbon (DOC),the specific UV absorbance (SUVA),trihalomethanes formation potential (THMFP),organic halogen adsorbable on activated carbon formation potential (AOXFP) and parallel factor analysis of excitation–emission matrices (PARAFAC-EEMs).In the three UV-based AOPs,HPI fraction with low molecular weight and aromaticity was more likely to degradate than HPO and TPI,and the removal efficiency of SUVA for HPO was much higher than TPI and HPI fraction.In terms of the specific THMFP of HPO,TPI and HPI,a reduction was achieved in the UV/H_(2)O_(2)process,and the higest removal rate even reached to 83%.UV/TiO_(2)and UV/PS processes can only decrease the specific THMFP of HPI.The specific AOXFP of HPO,TPI and HPI fractions were all able to be degraded by the three UV-based AOPs,and HPO content is more susceptible to decompose than TPI and HPI content.UV/H_(2)O_(2)was found to be the most effective treatment for the removal of THMFP and AOXFP under given conditions.C1 (microbial or marine derived humic-like substances),C_(2) (terrestrially derived humic-like substances)and C_(3) (tryptophan-like proteins) fluorescent components of HPO fraction were fairly labile across the UV-based AOPs treatment.C_(3) of each fraction of NOM was the most resistant to degrade upon the UV-based AOPs.Results from this study may provide the prediction about the consequence of UV-based AOPs for the degradation of different fractions of NOM with varied characteristics.

关键词： Advanced oxidation processes Natural organic matter Trihalomethanes Organic halogen adsorbable on activated carbon Parallel factor analysis

Accretion Processes of Oceanic Crust in Slow-spreading Ridges:Plagiogranite Perspective of the Xigaze Ophiolite,South Tibet

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Acta Geologica Sinica(English Edition) 2022年第6期96卷 1945-1959页

作者： LI Yuan LI ruibao YANG Shengbiao ZHANG Jian YANG Jingsui Institute of Geology Chinese Academy of Geological SciencesBeijing 100037China School of Earth Sciences and Resources Chang’an UniversityXi’an 710054China Tianjin Institute of Geology and Mineral Resources Tianjing 300170China School of Earth Sciences and Engineering Nanjing UniversityNanjing 210023China

Structural and petrological data suggest that the Xigaze ophiolite from the Yarlung Zangbo Suture Zone(YZSZ)in south Tibet was a typical slow-spreading ridge.A new field,geochemical,mineral,and U-Pb zircon dataset of plagiogranite intrusions were used to constrain the dynamic processes of oceanic accretion in this slow-spreading ridge.Plagiogranites mainly occur as dykes or intrusions intruded into the whole sequence of the ophiolite and have a similar orientation to the dolerite dykes developed in the late stage of detachment faulting.U-Pb zircon ages of 122–123 Ma were obtained for two types of plagiogranites and associated dolerite dykes.Detailed geochemical and mineralogical examinations suggest that the plagiogranites are the product of low-pressure(2–3 kbar)fractional crystallization of midocean ridge basalt-like magma and unlikely to have been derived from the partial melting of hydrous gabbroic rocks.The complex cross-cut relationship between the plagiogranites and ophiolite sequence reflects that they are controlled by small discontinued melt lenses rather than a big magma chamber under the ridge axis and reveals multiple injections during the oceanic crust accretion.The formation of plagiogranites possibly reflects the complex characteristic of oceanic accretion at slow-spreading ridges,time-dependent on structural(external)and magmatic(internal)processes.

关键词： Xigaze ophiolite plagiogranite fractional crystallization multiple magma injection ocean-continent transition zone

The Boninite-like Dolerites in the Xigaze Ophiolites, Tibet: Similar to the MORB-like Dolerites

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Acta Geologica Sinica(English Edition) 2020年第S01期94卷 73-75页

作者： YANG Shengbiao YANG Jingsui LI Yuan LI ruibao Center for Advanced Research on the Mantle(CARMA) Key Laboratory of Deep-Earth Dynamics of Ministry of Land and ResourcesInstitute of GeologyChinese Academy of Geological SciencesBeijing 100037 School of Earth Sciences and Resources Chang’an UniversityXi’anShaanxi 710054

The Early Cretaceous Xigaze ophiolites(XO)exposed along the central segment of the more than 2000 km long Yarlung Zangbo Suture Zone in southern Tibet,preserved the structure of the upper mantle and oceanic crust,is interpreted as a definite record of Neo-Tethys oceanic lithosphere.Many evolution models of the XO have been proposed since the 1980s(Nicolas et al.,1981;Hébert et al.,2012;Maffione et al.,2015).However,the geodynamic environment of the XO whether at a MOR or SSZ remains controversial.As key evidence for the identification of the SSZ ophiolite,the boninite-like dolerites from the XO are still controversial and poorly constraint(Chen et al.,2003;Bao et al.,2013;Dai et al.,2013).According to previous reports,dolerites were subdivided to MORB-like type and boninite-like type(Chen et al.,2003;Dai et al.,2013).Apart from high-SiO2(>52 wt%),high MgO(>8 wt%)and low-TiO2(rength elements(HFSE,Nb,Ta)(Fig.1).Boninite-like dolerites resemble the MORB-like dolerites in trace elements and REE patterns,excepting for lower concentrations in REE,but distinct from the boninites discovered from the IBM or Troodos ophiolite(Fig.1c,d).Th in both dolerites deviate from the MORB array with negative slopes on the Th/Yb vs.Nb/Yb diagram(Fig.2a),suggesting constant subduction component added to the mantle source(Pearce et al.,1995).We chose depleted MORB source Mantle(DMM,Workman and Hart,2005)as the starting composition computing immobile element contents for primary melts using the methods and partition coefficients o

关键词： Yarlung Zangbo suture zone Xigaze ophiolite depleted mantle mid-ocean ridge

RBM46 is essential for gametogenesis and functions in post-transcriptional roles affecting meiotic cohesin subunits

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Protein & Cell 2023年第1期14卷 51-63页

作者： Yue Lv Gang Lu Yuling Cai ruibao Su Liang Liang Xin Wang Wenyu Mu Xiuqing He Tao Huang Jinlong Ma Yueran Zhao Zi-Jiang Chen Yuanchao Xue Hongbin Liu Wai-Yee Chan Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan 250012China Center for Reproductive Medicine Shandong UniversityJinan 250012China CUHK-SDU Joint Laboratory on Reproductive Genetics School of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongHong KongChina Key Laboratory of Reproductive Endocrinology of Ministry of Education Shandong UniversityJinan 250012China Key Laboratory of RNA Biology Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Fertility Preservation Lab Reproductive Medicine CenterGuangdong Second Provincial General HospitalGuangzhou 510062China Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics Shanghai 200135China Center for Reproductive Medicine Ren Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200135China

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis,but the targets and molecular functions of RBM46 remain unknown.Here,we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation.Using a recently reported,high-resolution technique known as LACE-seq and working with low-input cells,we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes.We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions.In Rbm46 knockout mice,the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation,resulting in the failed assembly of axial elements,synapsis disruption,and meiotic arrest.Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.

关键词： RBM46 LACE-seq RNA-binding protein meiosis cohesin