High‐grade B‐cell lymphoma not otherwise specified, with diffuse large B‐cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics

High‐grade B‐cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. 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 = 55) in adults (n = 45) and in children (n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL (n = 85) and BL (n = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene‐expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB‐ or ABC‐like mRNA signatures and exhibit higher genomic complexity, similar to de novo DLBCL, and show alteration in genes regulating B‐cell activation (CD79B, MYD88, PRDM1, TBLIXR1, CARD11), epigenome (KMT2D, TET2) and cell cycle transition (TP53, ASPM). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL‐NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B‐cell activation (del‐PRDM1, gain‐BCL6, ‐REL, ‐STAT3) and cell cycle regulators (del‐TP53, del‐CDKN2A, del‐RB1, gain‐CCND3) were observed. Pediatric cases showed GCB‐DLBCL‐like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic PIM1 mutations were present in adult HGBCL, NOS. In vitro analyses with pharmacologic or genetic inhibition of PIM1 expression triggered B‐cell activation and NF‐κB‐induced apoptosis, suggesting that PIM1 is a rational therapeutic target.