title: The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma.
abstract: Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30.4% of FL cases that was associated with weak elevation of transcript levels. PCR-Sanger analysis did not show any somatic mutation in FL tumors. In support of a marginal oncogenic role, a REL-transduced FL cell line was positively selected under limiting serum conditions. Interestingly, reanalysis of previously reported gene expression profiles revealed significant enrichment of DNA damage-induced repair and cell cycle arrest pathways in tFL tumors with high REL expression compared to those with low REL expression consistent with the critical role of c-REL in genotoxicity-induced NF-κB signaling, which was reported to lead to drug resistance. In addition to DNA damage repair genes such as ATM and BRCA1, anti-apoptotic BCL2 was significantly elevated in REL-high FL and tFL tumors. Altogether these data suggest that other genes located in amplified 2p16.1-p15 locus may have more oncogenic role in FL etiology; however, high REL expression may be useful as a predictive biomarker of response to immunochemotherapy, and inhibition of c-REL may potentially sensitize resistant FL or tFL cells to chemotherapy.
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Hu
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Baytak
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu, Guangxi, China.
authors.forename: Jinnan
authors.initials: J
authors.lastname: Li
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey.
authors.forename: Burcu
authors.initials: B
authors.lastname: Akman
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey.
authors.forename: Kaan
authors.initials: K
authors.lastname: Okay
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey; Department of Clinical Medicine, Guilin Medical University, Guangxi, China.
authors.forename: Genfu
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu, Guangxi, China. Electronic address: zhangwyliu@163.com.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: İzmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, İzmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey. Electronic address: can.kucuk@deu.edu.tr.
authors.forename: Can
authors.initials: C
authors.lastname: Küçük
mesh_terms: D001706:Biopsy; D059447:Cell Cycle Checkpoints / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D020573:Genes, rel / Q000502:physiology*; D006801:Humans; D008224:Lymphoma, Follicular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D000090063:Proto-Oncogene Mas
chemical_list: C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas
keywords: Amplification; Chemoresistance; Genotoxicity-induced NF-κB pathway; REL; tFL