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Recently, an activating mutation in the DNA\u2010binding domain of IRF4 (IRF4<jats:sup>K59R<\/jats:sup>) was found as a recurrent somatic mutation in ATLL patients. However, it remains unknown how this mutation gives rise to the observed oncogenic effect. To understand the mode of IRF4<jats:sup>K59R<\/jats:sup>\u2010mediated gain of function in ATLL pathogenesis, we have determined the structural and affinity basis of IRF4<jats:sup>K59R<\/jats:sup>\/DNA homodimer complex using X\u2010ray crystallography and surface plasmon resonance. Our study shows that arginine substitution (R59) results in the reorientation of the side chain, enabling the guanidium group to interact with the phosphate backbone of the DNA helix. This markedly contrasts with the IRF4<jats:sup>WT<\/jats:sup> wherein the K59 interacts exclusively with DNA bases. Further, the arginine mutation causes enhanced DNA bending, enabling the IRF4<jats:sup>K59R<\/jats:sup> to interact more robustly with known DNA targets, as evidenced by increased binding affinity of the protein\u2013DNA complex. Together, we demonstrate how key structural features underpin the basis for this activating mutation, thereby providing a molecular rationale for IRF4<jats:sup>K59R<\/jats:sup>\u2010mediated ATLL development.<\/jats:p>","DOI":"10.1002\/pro.4260","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T12:29:27Z","timestamp":1639657767000},"page":"787-796","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The molecular basis for the development of adult T\u2010cell leukemia\/lymphoma in patients with an <scp>IRF4<sup>K59R<\/sup><\/scp> mutation"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-2454","authenticated-orcid":false,"given":"Srinivasan","family":"Sundararaj","sequence":"first","affiliation":[{"name":"John Curtin School of Medical Research Australian National University  Canberra Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5626-7968","authenticated-orcid":false,"given":"Sandali","family":"Seneviratne","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research Australian National University  Canberra Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4781-6261","authenticated-orcid":false,"given":"Simon J","family":"Williams","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-6463","authenticated-orcid":false,"given":"Anselm","family":"Enders","sequence":"additional","affiliation":[{"name":"Department of Immunology, John Curtin School of Medical Research Australian National University  Canberra Australia"},{"name":"Center for Personalised 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