After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggre...After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.展开更多
Mutations in the plant homeodomain-like finger protein 6(PHF6)gene are strongly associated with acute myeloid(AML)and T-cell acute lymphoblastic leukemia(T-ALL).In this study,we demonstrated that PHF6 can bind to H3K9...Mutations in the plant homeodomain-like finger protein 6(PHF6)gene are strongly associated with acute myeloid(AML)and T-cell acute lymphoblastic leukemia(T-ALL).In this study,we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus.The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci,resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription.The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner,thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription.The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci,resulting in an increase in rDNA transcription activity,the proliferation of in vitro leukemia cells,and the growth of in vivo mouse xenografts.Importantly,significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6.The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine,the drug that is most commonly used to treat AML.Collectively,we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.展开更多
Objective: T-cell lymphoblastic lymphoma(T-LBL) is an aggressive neoplasm of precursor T cells, however,detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of t...Objective: T-cell lymphoblastic lymphoma(T-LBL) is an aggressive neoplasm of precursor T cells, however,detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of this study was to identify putative driver genes in T-LBL.Methods: To gain insight into the genetic mechanisms of T-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with T-LBL.Results: We identified 32 putative driver genes using whole-exome sequencing in 41 T-LBL cases, many of which have not previously been described in T-LBL, such as Janus kinase 3(JAK3), Janus kinase 1(JAK1), Runtrelated transcription factor 1(RUNX1) and Wilms’ tumor suppressor gene 1(WT1). When comparing the genetic alterations of T-LBL to T-cell acute lymphoblastic leukemia(T-ALL), we found that JAK-STAT and RAS pathway mutations were predominantly observed in T-LBL(58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in T-ALL. Notably, besides notch receptor 1(NOTCH1), mutational status of plant homeodomain(PHD)-like finger protein 6(PHF6) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL.Conclusions: Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.展开更多
基金financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306)Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18)+1 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014)Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004)
文摘After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.
基金supported by the National Natural Science Foundation of China (81702750, 81670141, 81970145and 82001698)Natural Science Foundation of Guangdong Province (2020A1515011465and 2020A151501467, China)+5 种基金Science, Technology & Innovation Commission of Shenzhen Municipality ( JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, JCYJ20190807151609464, JCYJ20200109142605909 and JCYJ20210324120007020, China)Sun Yat-sen University (20ykzd17 and 20ykpy122, China)International Collaboration of Science and Technology of Guangdong Province (2020A0505100031, China)Guangdong Provincial Key Laboratory of Digestive Cancer Research (No.2021B1212040006,China)The Social Development Foundation of Jiangsu Province (BE2018691, China)Sigrid Jusélius foundation in Finland for funding the project (Finland)
文摘Mutations in the plant homeodomain-like finger protein 6(PHF6)gene are strongly associated with acute myeloid(AML)and T-cell acute lymphoblastic leukemia(T-ALL).In this study,we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus.The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci,resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription.The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner,thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription.The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci,resulting in an increase in rDNA transcription activity,the proliferation of in vitro leukemia cells,and the growth of in vivo mouse xenografts.Importantly,significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6.The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine,the drug that is most commonly used to treat AML.Collectively,we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.
基金supported by the National Natural Science Foundation of China (No. U1904139 and 82070209)。
文摘Objective: T-cell lymphoblastic lymphoma(T-LBL) is an aggressive neoplasm of precursor T cells, however,detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of this study was to identify putative driver genes in T-LBL.Methods: To gain insight into the genetic mechanisms of T-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with T-LBL.Results: We identified 32 putative driver genes using whole-exome sequencing in 41 T-LBL cases, many of which have not previously been described in T-LBL, such as Janus kinase 3(JAK3), Janus kinase 1(JAK1), Runtrelated transcription factor 1(RUNX1) and Wilms’ tumor suppressor gene 1(WT1). When comparing the genetic alterations of T-LBL to T-cell acute lymphoblastic leukemia(T-ALL), we found that JAK-STAT and RAS pathway mutations were predominantly observed in T-LBL(58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in T-ALL. Notably, besides notch receptor 1(NOTCH1), mutational status of plant homeodomain(PHD)-like finger protein 6(PHF6) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL.Conclusions: Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.
