{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T21:57:52Z","timestamp":1775858272123,"version":"3.50.1"},"reference-count":45,"publisher":"Cold Spring Harbor Laboratory","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:p>Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of<jats:italic>CD79B<\/jats:italic>,<jats:italic>MyD88<\/jats:italic>,<jats:italic>TP53<\/jats:italic>,<jats:italic>TBL1XR1<\/jats:italic>, and<jats:italic>PIM1<\/jats:italic>genes, indicating that this lymphoma would be best classified as MCD\/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of<jats:italic>TP53<\/jats:italic>heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as<jats:italic>PRDM1<\/jats:italic>loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of<jats:italic>BTK<\/jats:italic>and<jats:italic>FOXO1<\/jats:italic>mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.<\/jats:p>","DOI":"10.1101\/mcs.a006283","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T22:15:13Z","timestamp":1695248113000},"page":"a006283","source":"Crossref","is-referenced-by-count":5,"title":["Leukemic presentation and progressive genomic alterations of MCD\/C5 diffuse large B-cell lymphoma (DLBCL)"],"prefix":"10.1101","volume":"9","author":[{"given":"Patricia M.","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reza","family":"Nejati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devang","family":"Thakkar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Mackrides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Dupoux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shazia","family":"Nakhoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Don A.","family":"Baldwin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianming","family":"Pei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep S.","family":"Dave","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. 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