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In B\u2010cell acute lymphoblastic leukemia (B\u2010ALL), double homeobox 4 fused with immunoglobulin heavy chain (DUX4\/IGH) can lead to the aberrant production of E\u201026 transformation\u2010specific family related gene abnormal transcript (ERG\n                      <jats:sub>alt<\/jats:sub>\n                      ) and other splicing variants. However, the molecular mechanism underpinning this process remains elusive. Here, we aimed to know how DUX4\/IGH triggers abnormal splicing in leukemia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      The differential intron retention analysis was conducted to identify novel DUX4\/IGH\u2010driven splicing in B\u2010ALL patients. X\u2010ray crystallography, small angle X\u2010ray scattering (SAXS), and analytical ultracentrifugation were used to investigate how DUX4\/IGH recognize double DUX4 responsive element (DRE)\u2010DRE sites. The ERG\n                      <jats:sub>alt<\/jats:sub>\n                      biogenesis and B\u2010cell differentiation assays were performed to characterize the DUX4\/IGH crosslinking activity. To check whether recombination\u2010activating gene 1\/2 (RAG1\/2) was required for DUX4\/IGH\u2010driven splicing, the proximity ligation assay, co\u2010immunoprecipitation, mammalian two hybrid characterizations, in vitro RAG1\/2 cleavage, and shRNA knock\u2010down assays were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We reported previously unrecognized intron retention events in C\u2010type lectin domain family 12, member A abnormal transcript (CLEC12A\n                      <jats:sub>alt<\/jats:sub>\n                      ) and chromosome 6 open reading frame 89 abnormal transcript (C6orf89\n                      <jats:sub>alt<\/jats:sub>\n                      ), where also harbored repetitive DRE\u2010DRE sites. Supportively, X\u2010ray crystallography and SAXS characterization revealed that DUX4 homeobox domain (HD)1\u2010HD2 might dimerize into a dumbbell\u2010shape trans configuration to crosslink two adjacent DRE sites. Impaired DUX4\/IGH\u2010mediated crosslinking abolishes ERG\n                      <jats:sub>alt<\/jats:sub>\n                      , CLEC12A\n                      <jats:sub>alt<\/jats:sub>\n                      , and C6orf89\n                      <jats:sub>alt<\/jats:sub>\n                      biogenesis, resulting in marked alleviation of its inhibitory effect on B\u2010cell differentiation. Furthermore, we also observed a rare RAG1\/2\u2010mediated recombination signal sequence\u2010like DNA edition in DUX4\/IGH target genes. Supportively, shRNA knock\u2010down of RAG1\/2 in leukemic Reh cells consistently impaired the biogenesis of ERG\n                      <jats:sub>alt<\/jats:sub>\n                      , CLEC12A\n                      <jats:sub>alt<\/jats:sub>\n                      , and C6orf89\n                      <jats:sub>alt<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">All these results suggest that DUX4\/IGH\u2010driven DNA crosslinking is required for RAG1\/2 recruitment onto the double tandem DRE\u2010DRE sites, catalyzing V(D)J\u2010like recombination and oncogenic splicing in acute lymphoblastic leukemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12234","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T15:43:20Z","timestamp":1635263000000},"page":"1116-1136","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["DNA crosslinking and recombination\u2010activating genes 1\/2 (RAG1\/2) are required for oncogenic splicing in acute lymphoblastic leukemia"],"prefix":"10.34133","volume":"41","author":[{"given":"Hao","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai JiaoTong University","place":["Shanghai, P. 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Nat Genet. 2019;51((6)):947\u201351.","journal-title":"Nat Genet"},{"issue":"8","key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.3324\/haematol.2020.250423","article-title":"DUX4r, ZNF384r and PAX5\u2010P80R mutated B\u2010cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch","volume":"106","author":"Michaela N","year":"2020","unstructured":"Michaela N, Marketa Z, Karel F, Barbora V, Lucie S, Alena M, et\u00a0al. DUX4r, ZNF384r and PAX5\u2010P80R mutated B\u2010cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch. Haematologica. 2020;106((8)):2066\u201375.","journal-title":"Haematologica"},{"issue":"2","key":"e_1_3_2_13_2","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41588-018-0315-5","article-title":"PAX5\u2010driven subtypes of B\u2010progenitor acute lymphoblastic leukemia","volume":"51","author":"Gu Z","year":"2019","unstructured":"Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et\u00a0al. PAX5\u2010driven subtypes of B\u2010progenitor acute lymphoblastic leukemia. Nat Genet. 2019;51((2)):296\u2013307.","journal-title":"Nat Genet"},{"issue":"1","key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13059-017-1184-4","article-title":"IRFinder: assessing the impact of intron retention on mammalian gene expression","volume":"18","author":"Middleton R","year":"2017","unstructured":"Middleton R, Gao D, Thomas A, Singh B, Au A, Wong JJ, et\u00a0al. IRFinder: assessing the impact of intron retention on mammalian gene expression. 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