Waseem G. Lone, University of Nebraska Medical CenterFollow
Alyssa Bouska, University of Nebraska Medical CenterFollow
Tyler A. Herek, University of Nebraska Medical Center
Catalina Amador, University of Miami
Joo Song, City of Hope National Medical Center
Alexander M. Xu, Cedars-Sinai Medical Center and Samuel Oschin Comprehensive Cancer Institute
Dylan T. Jochum, University of Nebraska Medical CenterFollow
Issa Ismail Issa, University of Nebraska Medical Center
Dennis D. Weisenburger, University of Nebraska Medical CenterFollow
Xuan Zhang, University of Nebraska Medical Center
Sharath Kumar Bhagavathi, University of Iowa
Tayla B. Heavican-Foral, Dana-Farber Cancer Institute
Sunandini Sharma, University of Nebraska Medical Center
Ab Rauf Shah, University of Nebraska Medical CenterFollow
Abdul Rouf Mir, University of Nebraska Medical CenterFollow
Aisha Ahmad Alkhinji, University of Nebraska Medical Center
Dalia El-Gamal, University of Nebraska Medical CenterFollow
Bhavana J. Dave, University of Nebraska Medical Center
Keenan Hartert, Minnesota State University, Mankato
Jiayu Yu, University of Nebraska Medical Center
Mallick Saumyaranjan, All India Institute of Medical Sciences
Timothy C. Greiner, University of Nebraska Medical Center
Julie M. Vose, University of Nebraska Medical CenterFollow
Timothy W. McKeithan, City of Hope National Medical Center
Kai Fu, Roswell Park Comprehensive Cancer Center
Michael Green, University of Texas MD Anderson Cancer Center
Chengfeng Bi, University of Nebraska Medical Center
Akil Merchant, Cedars-Sinai Medical Center and Samuel Oschin Comprehensive Cancer Institute
Wing C. Chan, City of Hope National Medical Center
Javeed Iqbal, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

American Journal of Hematology

Publication Date

2024

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.

ISSN

1096-8652

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Download

Share

COinS