Multiple myeloma(MM)is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability(CIN),which contributes to the acquisition of heterogeneity,along with MM progression,drug resistanc...Multiple myeloma(MM)is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability(CIN),which contributes to the acquisition of heterogeneity,along with MM progression,drug resistance,and relapse.In this study,we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes.Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo,while genetic targeting BUB1B abrogated this effect.Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170.Interestingly,we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B,which was translated by a circular RNA of BUB1B.The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN.In addition,MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein.Intriguingly,BUB1B siRNA,targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa,significantly inhibited MM malignancy in vitro and in vivo.Collectively,BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.展开更多
Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development o...Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development of vaccines with broad protective effects.In this study,we selected hotspot mutations in the receptor-binding domain(RBD)that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein(cRBD),and we found cRBDs have broad protective effects against SARS-CoV-2 variants.Three cRBDs were designed in our study.Compared with the BA.1 RBD protein,the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies,suggesting stronger and broader protective efficacy.In viral challenge experiments,cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury.Among the three constructs,cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine.In conclusion,immunization with cRBDs triggered immunity against a wide range of variants,including those that emerged after we had completed designing the cRBDs.This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.展开更多
基金This work was supported by National Key R&D Program of China(2020YFA0509400)(to Y.Y.)National Natural Science Foundation of China 81970196(to C.G.)and 82073885(to Y.Y.)+1 种基金Natural Science Foundation of Jiangsu Province BK20200097(to C.G.)Jiangsu Postgraduate Research and Practice Innovation Program KYCX20_1479(to X.T.)and KYCX21_1769(to R.W.).
文摘Multiple myeloma(MM)is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability(CIN),which contributes to the acquisition of heterogeneity,along with MM progression,drug resistance,and relapse.In this study,we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes.Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo,while genetic targeting BUB1B abrogated this effect.Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170.Interestingly,we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B,which was translated by a circular RNA of BUB1B.The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN.In addition,MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein.Intriguingly,BUB1B siRNA,targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa,significantly inhibited MM malignancy in vitro and in vivo.Collectively,BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.
基金supported by the Key Project of applied basic research in Yunnan Province(202401AS070049)CAMS Innovation Fund for Medical Sciences(2021-I2M-1-038,2022-I2M-CoV19-002)+1 种基金National Key R&D Program of China(2021YFC230170402)Yunnan Key R&D Project(202103AQ100001).
文摘Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development of vaccines with broad protective effects.In this study,we selected hotspot mutations in the receptor-binding domain(RBD)that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein(cRBD),and we found cRBDs have broad protective effects against SARS-CoV-2 variants.Three cRBDs were designed in our study.Compared with the BA.1 RBD protein,the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies,suggesting stronger and broader protective efficacy.In viral challenge experiments,cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury.Among the three constructs,cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine.In conclusion,immunization with cRBDs triggered immunity against a wide range of variants,including those that emerged after we had completed designing the cRBDs.This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.
