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Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200955) in adults (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200945) and in children (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with\n                    <jats:italic>de novo<\/jats:italic>\n                    DLBCL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200985) and BL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200952). This subgroup, representing ~60% of HGBCL, NOS, lack gene\u2010expression signature of BL and double hit\/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB\u2010 or ABC\u2010like mRNA signatures and exhibit higher genomic complexity, similar to\n                    <jats:italic>de novo<\/jats:italic>\n                    DLBCL, and show alteration in genes regulating B\u2010cell activation (\n                    <jats:italic>CD79B<\/jats:italic>\n                    ,\n                    <jats:italic>MYD88<\/jats:italic>\n                    ,\n                    <jats:italic>PRDM1<\/jats:italic>\n                    ,\n                    <jats:italic>TBLIXR1<\/jats:italic>\n                    ,\n                    <jats:italic>CARD11<\/jats:italic>\n                    ), epigenome (\n                    <jats:italic>KMT2D<\/jats:italic>\n                    ,\n                    <jats:italic>TET2<\/jats:italic>\n                    ) and cell cycle transition (\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>ASPM<\/jats:italic>\n                    ). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL\u2010NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B\u2010cell activation (del\u2010\n                    <jats:italic>PRDM1<\/jats:italic>\n                    , gain\u2010\n                    <jats:italic>BCL6<\/jats:italic>\n                    , \u2010\n                    <jats:italic>REL<\/jats:italic>\n                    , \u2010\n                    <jats:italic>STAT3<\/jats:italic>\n                    ) and cell cycle regulators (del\u2010\n                    <jats:italic>TP53<\/jats:italic>\n                    , del\u2010\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    , del\u2010\n                    <jats:italic>RB1<\/jats:italic>\n                    , gain\u2010\n                    <jats:italic>CCND3<\/jats:italic>\n                    ) were observed. Pediatric cases showed GCB\u2010DLBCL\u2010like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic\n                    <jats:italic>PIM1<\/jats:italic>\n                    mutations were present in adult HGBCL, NOS.\n                    <jats:italic>In vitro<\/jats:italic>\n                    analyses with pharmacologic or genetic inhibition of\n                    <jats:italic>PIM1 expression<\/jats:italic>\n                    triggered B\u2010cell activation and NF\u2010\u03baB\u2010induced apoptosis, suggesting that\n                    <jats:italic>PIM1<\/jats:italic>\n                    is a rational therapeutic target.\n                  <\/jats:p>","DOI":"10.1002\/ajh.27513","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T04:38:30Z","timestamp":1731731910000},"page":"10-22","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["High\u2010grade B\u2010cell lymphoma not otherwise specified, with diffuse large B\u2010cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-614X","authenticated-orcid":false,"given":"Waseem","family":"Lone","sequence":"first","affiliation":[{"name":"Pathology, Microbiology and Immunology University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Bouska","sequence":"additional","affiliation":[{"name":"Pathology, Microbiology and Immunology University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler A.","family":"Herek","sequence":"additional","affiliation":[{"name":"Pathology, Microbiology and Immunology University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Amador","sequence":"additional","affiliation":[{"name":"Department of Pathology 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