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Acute lymphoblastic leukemia (ALL) is a hematologic malignancy caused by the clonal proliferation of lymphoid stem progenitor cells, and it is the most common type of leukemia in children.Recently, Ruijin Hospital, Shanghai institute of hematology, state key laboratory of medical genomics Meng Guoyu team and Chen Saijuanteamwork, for acute B lymphocytic leukemia gene DUX4 / IGH launched a series of research, clarified the DUX4 / IGH how to drive B - ALL the specific molecular and structural biology of the disease.The results were published in Leukemia (IF=~12), a well-known journal in the field of hematology.
Located on the 4th telomeres DUX4 gene sequence is inserted into the chromosome 14 of immunoglobulin heavy chain (IGH) interior, forming DUX4 / IGH fusion gene and express abnormally high, its existence is B - an important new classification of ALL markers.DUX4 protein is a bihomologous cassette transcription factor, which contains two homologous structural domains of DNA, HD1 and HD2, and CTD structural domains of carbon recruitment related transcription factors.Abnormal expression of DUX4 was previously reported in facial shoulder brachial muscular dystrophy (FSHD).In this study, Meng Guoyu‘s team analyzed chip-seq data and discovered the core DNA sequence of DUX4 binding to downstream target genes.The team bold assumption, DUX4 protein/IGH carcinoma combined with target gene may be the pathogenesis of leukemia important node, and through structural biology for the important breakthrough point, to explore the pathogenesis of DUX4 / IGH cause leukemia.The applicant team first identified two different DUX4 structures by means of crystallography, namely apo-dux4 without binding to DNA substrate and dux4-dna complex with DNA binding.Then, the way in which DUX4/IGH binds to the target gene (TAATCTAAT) and the spatial site of interaction are confirmed by structural comparison.On the basis of structural biology, functional verification was carried out at the molecular, cellular and animal levels through targeted mutation.Consistent results, points out that DUX4 - the combination of DNA has very important significance of leukemia incidence: destroy DUX4 with the combination of DNA will seriously restrain DUX4 / IGH activation of target genes, undermine DUX4 / IGH restrain B cell differentiation, proliferation effect of protein function such as cancer.
This study partly explains the pathogenesis of DUX4/IGH in b-all.Changing or inhibiting its interaction with DNA may inhibit the occurrence of leukemia, thus providing a new target for the treatment of leukemia and a new idea for the treatment of leukemia.Meng Guoyu and Chen Saijuan are the co-corresponding authors of this paper. Dong Xue, Zhang weina, Wu Haiyan, and Huang Jinyan, are the co-first authors.