DEK Regulates B-Cell Proliferative Capacity and Is Associated with Aggressive Disease in Low-Grade B-Cell Lymphoma

Introduction: Non-Follicular Low-Grade B-Cell Lymphomas (LGBCL) are a subset of lymphomas that share overlapping clinical and histologic features. While most cases of LGBCL have an indolent course, some experience aggressive disease with no definitive biomarkers to identify aggressive cases at diagn...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.4360-4360
Main Authors: Hopper, Melissa A., Dropik, Abigail R., Walker, Janek S., Novak, Joseph P., Laverty, Miranda S., Manske, Michelle, Wu, Xiaosheng, Wenzl, Kerstin, Krull, Jordan Edward, Sarangi, Vivekananda, Maurer, Matthew J., Habermann, Thomas M., Link, Brian K., Rimsza, Lisa M., Witzig, Thomas E., Ansell, Stephen M, Cerhan, James R., Jevremovic, Dragan, Novak, Anne J.
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Language:English
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Summary:Introduction: Non-Follicular Low-Grade B-Cell Lymphomas (LGBCL) are a subset of lymphomas that share overlapping clinical and histologic features. While most cases of LGBCL have an indolent course, some experience aggressive disease with no definitive biomarkers to identify aggressive cases at diagnosis. Significant advances have been made in the molecular classification of other lymphomas, yet molecular profiling and identification of mechanisms driving aggressive disease in LGBCL remain an unmet need. We previously used a multi-omic approach to characterize the molecular and immune landscapes of LGBCL tumors and identified a transcriptomic signature associated with cell proliferation and inferior overall survival (OS) in two independent cohorts (HR 7.82; 95% CI 2.4-25.4; p < 0.001 & HR 10.07; 95% CI 2.00-50.61; p = 0.005) and cases that transformed to DLBCL (Hopper et al., 2023). Here, we identify the oncoprotein DEK as a novel transcriptional regulator of this signature and use a functional genomic approach to further interrogate the role of DEK in B-cell lymphoma. Methods: Tumors from 64 newly-diagnosed/untreated LGBCL cases enrolled in the University of Iowa/Mayo Clinic Molecular Epidemiology Resource were included in this study (SMZL = 48, NMZL = 6, LPL = 5, B-NOS = 3, EMZL = 2). Tumor RNA-seq and paired tumor-normal WES were used to assess DEK expression and identify copy number alterations (CNAs), respectively. DEK deficient (KO) cell line models were generated using CRIPSR/Cas9. DEK expression was assessed by western blot (WB) and immunofluorescence (IF) using standard techniques. Proliferation was assessed by MTT assay. Results: To identify transcriptional regulators of our previously identified signature, we used the tool MAGIC to mine publicly available ChIP-seq data and identified DEK, an oncoprotein associated with tumorigenesis and poor prognosis in several cancers, as a key regulator of genes in our signature (p = 0.008). RNA-seq indicated that high levels of DEK expression associated with inferior OS in LGBCL (HR 2.99; 95% CI 1.21-7.36; p = 0.02). Additionally, we identified DEK as a target of copy number gains/amps in LGBCL (7% of cases), which corresponded to significantly higher DEK expression (p = 0.04). The association of DEK with aggressive lymphoma was confirmed when we assessed its expression in public cell line RNA-seq data and observed the highest expression in lines derived from aggressive lymphomas, which we further validated a
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-180232