{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:48:29Z","timestamp":1789213709552,"version":"build-2803163510"},"reference-count":11,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T00:00:00Z","timestamp":1528848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton\u2019s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-\u03baB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.<\/jats:p>","DOI":"10.3390\/ijms19061758","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T10:45:35Z","timestamp":1528886735000},"page":"1758","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy"],"prefix":"10.3390","volume":"19","author":[{"given":"Lucy C.","family":"Fox","sequence":"first","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costas K.","family":"Yannakou","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Ryland","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Lade","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dickinson","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda A.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry Miles","family":"Prince","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/modpathol.2013.156","article-title":"Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma","volume":"27","author":"Andrique","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1038\/jid.2012.102","article-title":"MYD88 Somatic Mutation Is a Genetic Feature of Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type","volume":"132","author":"Cappellen","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1001\/jamadermatol.2014.821","article-title":"High Frequency and Clinical Prognostic Value of MYD88 L265P Mutation in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg-Type","volume":"150","author":"Barbe","year":"2014","journal-title":"JAMA Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/nm.3884","article-title":"Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma","volume":"21","author":"Wilson","year":"2015","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1016\/j.jid.2017.04.010","article-title":"Identification of somatic mutations in primary cutaneous diffuse large B-cell lymphoma, leg-type by massive parallel sequencing","volume":"137","author":"Mareschal","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4049\/jimmunol.163.1.269","article-title":"Constitutive nuclear translocation of NF-\u03baB in B cells in the absence of I\u03baB degradation","volume":"163","author":"Doerre","year":"1999","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3109\/10428194.2013.793324","article-title":"IRF8 is associated with germinal center B-cell-like type of diffuse large B-cell lymphoma and exceptionally involved in translocation t(14;16)(q32.33;q24.1)","volume":"55","author":"Tinguely","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fimmu.2014.00511","article-title":"Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond","volume":"5","author":"Walsh","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1158\/1078-0432.CCR-13-2175","article-title":"Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome","volume":"20","author":"Alhejaily","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e275","DOI":"10.3324\/haematol.2016.161893","article-title":"Combination of ibrutinib and chemotherapy produced a durable remission in multiply relapsed diffuse large B cell lymphoma leg type with mutant MYD88 and wildtype CD79","volume":"102","author":"Deng","year":"2017","journal-title":"Haematologica"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1758\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:08:34Z","timestamp":1760195314000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,13]]},"references-count":11,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["ijms19061758"],"URL":"https:\/\/doi.org\/10.3390\/ijms19061758","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,13]]}}}