The discovery of IgZ,or its counterpart IgT,represents a novel immunoglobulin isotype(namedζorτ)found in teleosts,introducing a new member to the existing Ig classes(μ,δ,γ,α,andε)among vertebrates.The distincti...The discovery of IgZ,or its counterpart IgT,represents a novel immunoglobulin isotype(namedζorτ)found in teleosts,introducing a new member to the existing Ig classes(μ,δ,γ,α,andε)among vertebrates.The distinctive intrachromosomal organization of ighz and ighm loci implies the necessity of a distinct,mutually exclusive recombination process for the independent generation of IgZ and IgM isotypes.However,the molecular mechanisms governing this process remain elusive.In this study,we unveil the regulatory function of myocyte enhancer factor 2D(Mef2d)in the assembly of ighz genes through epigenetic modulation in a zebrafish model.Mechanistically,Mef2d selectively hinders the recombination of ighm locus in IgZ^(+)B cells by binding to the 3'Eμsite of the ighm locus and helping establish a repressive modification pattern of H3K4me0/H3K9me2/H3K27me2 in Dμ/Jμregions through recruiting the co-repressive Sin3/Hdac1 complex with the assistance of cohesin complex and Setdb1/Ezh2 methyltransferases.Consequently,this renders the Dμ/Jμregions inaccessible to Rag1/2,thus preventing ighm rearrangement.As a pivotal regulator for IgZ isotype production,Mef2d exhibits differential expression in committed IgZ^(+)B cells,a process regulated by the Il-7/Il-7r-mediated p38 Mapk signaling pathway.These results indicate the existence of a unique isotypic exclusion mechanism underlying recombination between ighz and ighm locus in teleosts.This mechanism highlights an unrecognized strategy for generating diverse isotypes in vertebrates,distinct from the well-established class switch recombination process.This study significantly contributes to our understanding of paradigms,diversifications,and the evolutionary history of vertebrate adaptive immunity.展开更多
B-cell acute lymphoblastic leukemia(B-ALL)is a malignant tumor originating from B-lineage lymphoid precursor cells.The incidence of B-ALL is about 80%in childhood acute leukemia and 20%in adults.In recent years,with s...B-cell acute lymphoblastic leukemia(B-ALL)is a malignant tumor originating from B-lineage lymphoid precursor cells.The incidence of B-ALL is about 80%in childhood acute leukemia and 20%in adults.In recent years,with standardized treatment guided by risk stratification,the long-term disease-free survival rate of children is about 80%,while that of adults is less than 40%.However,the specific pathogenesis of the newly identified B-ALL and the targeted therapy strategies have not been vigorously investigated.In this review,we highlight the recent breakthroughs in mechanistic studies and novel therapeutic options in DUX4-and MEF2D-subtype B-ALLs.展开更多
基金supported by grants from the National Natural Sci- ence Foundation of China ( 32173003 )the National Key Research and Development Program of China ( 2018YFD0900503 , 2018YFD0900505 ).
文摘The discovery of IgZ,or its counterpart IgT,represents a novel immunoglobulin isotype(namedζorτ)found in teleosts,introducing a new member to the existing Ig classes(μ,δ,γ,α,andε)among vertebrates.The distinctive intrachromosomal organization of ighz and ighm loci implies the necessity of a distinct,mutually exclusive recombination process for the independent generation of IgZ and IgM isotypes.However,the molecular mechanisms governing this process remain elusive.In this study,we unveil the regulatory function of myocyte enhancer factor 2D(Mef2d)in the assembly of ighz genes through epigenetic modulation in a zebrafish model.Mechanistically,Mef2d selectively hinders the recombination of ighm locus in IgZ^(+)B cells by binding to the 3'Eμsite of the ighm locus and helping establish a repressive modification pattern of H3K4me0/H3K9me2/H3K27me2 in Dμ/Jμregions through recruiting the co-repressive Sin3/Hdac1 complex with the assistance of cohesin complex and Setdb1/Ezh2 methyltransferases.Consequently,this renders the Dμ/Jμregions inaccessible to Rag1/2,thus preventing ighm rearrangement.As a pivotal regulator for IgZ isotype production,Mef2d exhibits differential expression in committed IgZ^(+)B cells,a process regulated by the Il-7/Il-7r-mediated p38 Mapk signaling pathway.These results indicate the existence of a unique isotypic exclusion mechanism underlying recombination between ighz and ighm locus in teleosts.This mechanism highlights an unrecognized strategy for generating diverse isotypes in vertebrates,distinct from the well-established class switch recombination process.This study significantly contributes to our understanding of paradigms,diversifications,and the evolutionary history of vertebrate adaptive immunity.
基金This work was supported by research grants 81970132,81770142,81800144,and 31800642 from National Natural Science Foundation of Chinaa research grant 20JC1410600 from Shanghai Science and Technology Committee+1 种基金Shanghai Guangci Translational Medical Research Development Foundationa research grant 20152504 from“Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support”,“The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institute of Higher Learning”,Samuel Waxman Cancer Research Foundation。
文摘B-cell acute lymphoblastic leukemia(B-ALL)is a malignant tumor originating from B-lineage lymphoid precursor cells.The incidence of B-ALL is about 80%in childhood acute leukemia and 20%in adults.In recent years,with standardized treatment guided by risk stratification,the long-term disease-free survival rate of children is about 80%,while that of adults is less than 40%.However,the specific pathogenesis of the newly identified B-ALL and the targeted therapy strategies have not been vigorously investigated.In this review,we highlight the recent breakthroughs in mechanistic studies and novel therapeutic options in DUX4-and MEF2D-subtype B-ALLs.
