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The recombination\u2010activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML\u2010LBC and <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild\u2010type (WT) RAG and catalytically inactive RAG\u2010expressing <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> and <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>\u2212<\/jats:sup> cell lines, respectively, and demonstrate that BCR\u2010ABL1 specifically collaborates with RAG recombinase to promote cell survival in\u00a0vitro and in xenograft mice models. WT RAG\u2010expressing <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> cell lines and primary CD34<jats:sup>+<\/jats:sup> bone marrow cells from CML\u2010LBC samples maintain more double\u2010strand breaks (DSB) compared to catalytically inactive RAG\u2010expressing <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> cell lines and RAG\u2010deficient CML\u2010CP samples, which are measured by \u03b3\u2010H2AX. WT RAG\u2010expressing <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> cells are biased to repair RAG\u2010mediated DSB by the alternative non\u2013homologous end joining pathway (a\u2010NHEJ), which could contribute genomic instability through increasing the expression of a\u2010NHEJ\u2010related MRE11 and RAD50 proteins. As a result, RAG\u2010expressing <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR\u2010ABL1 signaling but independent of the levels of BCR\u2010ABL1 expression and mutations in the BCR\u2010ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in <jats:italic>BCR\u2010ABL1<\/jats:italic><jats:sup>+<\/jats:sup> leukemia through its endonuclease activity.<\/jats:p>","DOI":"10.1111\/cas.14939","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T02:04:31Z","timestamp":1620180271000},"page":"2679-2691","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RAG enhances <i>BCR\u2010ABL1<\/i>\u2010positive leukemic cell growth through its endonuclease activity in vitro and in vivo"],"prefix":"10.1111","volume":"112","author":[{"given":"Meng","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences Xi\u2019an Jiaotong University Health Science Center Xi\u2019an 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