Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse

AIM： To examine the in vivo phenotype associated with hepatic metastatic lymph node 64 （MLN64） overexpression.METHODS： Recombinant-adenovirus-mediated MLN64 gene transfer was used to overexpress MLN64 in the livers of C57BL/6 mice. We measured the effects of MLN64 overexpression on hepatic cholesterol content, bile flow, biliary lipid secretion and apoptosis markers. For in vitro studies cultured CHO cells with transient MLN64 overexpression were utilized and apoptosis by TUNEL assay was measured.RESULTS： Livers from Ad.MLN64-infected mice exhibited early onset of liver damage and apoptosis. This response correlated with increases in liver cholesterol content and bilian/bile acid concentration, and impaired bile flow. We investigated whether liver MLN64 expression could be modulated in a murine model of hepatic injury. We found increased hepatic MLN64 mRNA and protein levels in mice with chenodeoxycholic acid-induced liver damage. In addition, cultured CliO cells with transient MLN64 overexpression showed increased apoptosis.CONCLUSION： In summary, hepatic MLN64 overexpression induced damage and apoptosis in murine livers and altered cholesterol metabolism. Further studies are required to elucidate the relevance of these findings under physiologic and disease conditions.

Role of Ikaros in T-cell acute lymphoblastic leukemia

Ikaros is a zinc finger transcriptional regulator encoded by the Ikzf1 gene.Ikaros displays crucial functions in the hematopoietic system and its loss of function has been linked to the development of lymphoid leukemia.In particular,Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia.Its role in T-cell leukemia,however,has been more controversial.While Ikaros deficiency appears to be very frequent in murine T-cell leukemias,loss of Ikaros appears to be rare in human T-cell acute lymphoblastic leukemia (T-ALL).We review here the evidence linking Ikaros to T-ALL in mouse and human systems.

A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes

Class switch recombination(CSR)occurs at the IgH locus and replaces the immunoglobulin(Ig)isotype expressed from IgM to IgG,IgE or IgA,endowing the B cell receptor with novel effector functions.CSR is triggered by activation-induced cytidine deaminase(AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by transcription.The distinct antibody isotypes are encoded in the IgH locus in individual transcription units composed of a cytokine-inducible promoter,an intronic exon,and a switch region(Sx),followed by the exons encoding the constant region(Cx)(Fig.S1a).During CSR,the choice of recombination to a particular isotype is determined by the stimulation-dependent activation of specific promoters,triggering the generation of noncoding germline transcripts(GLTs).2 Thus far,the transcriptional regulation of the IgH locus is known to be controlled by the Eμenhancer,located downstream of the variable region and upstream of the donor switch region(Sμ),and the 3′regulatory region(3′RR)super-enhancer located downstream of Cα.