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

in American journal of hematology by Waseem Lone, Alyssa Bouska, Tyler A Herek, Catalina Amador, Joo Song, Alexander M Xu, Dylan Jochum, Issa Ismail Issa, Dennis D Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B Heavican-Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El-Gamal, Bhavana J Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C Greiner, Julie Vose, Timothy W McKeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C Chan, Javeed Iqbal

TLDR

  • This study characterizes high-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) by analyzing its genetic and molecular features and identifies PIM1 as a potential therapeutic target.

Abstract

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.

Overview

  • The study aims to characterize high-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) by analyzing gene expression profiling (GEP), genomic DNA copy number (CN), and mutational spectrum in adults and children.
  • The study includes a cohort of 55 HGBCL, NOS patients, with 45 adults and 10 children, and compares their GEP, CN, and mutational spectrum with de novo diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).
  • The primary objective is to identify the genetic and molecular characteristics of HGBCL, NOS and potentially develop targeted therapies.

Comparative Analysis & Findings

  • The study found that HGBCL, NOS lacks gene-expression signature of BL and double hit/dark zone lymphoma, but expresses DLBCL-like signatures and is characterized by either GCB- or ABC-like mRNA signatures.
  • HGBCL, NOS exhibits higher genomic complexity, similar to de novo DLBCL, and shows alterations in genes regulating B-cell activation, epigenome, and cell cycle transition.
  • The study identified recurrent mutations in genes often mutated in BL, but rare in DLBCL, and frequent genomic CN alterations in genes regulating B-cell activation and cell cycle regulators.

Implications and Future Directions

  • The study highlights the genetic heterogeneity of HGBCL, NOS, which may have implications for personalized therapy and clinical management.
  • The identification of PIM1 as a potential therapeutic target suggests that targeting this gene may be a promising strategy for treating HGBCL, NOS.
  • Future studies should aim to validate these findings in larger cohorts and explore the potential of PIM1 inhibition as a therapeutic approach.
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