Establishment and characterization of a novel vincristine‐resistant diffuse large B‐cell lymphoma cell line containing the 8q24 homogeneously staining region

Abstract

Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT 1 , which lies adjacent to MYC , has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU ‐ ML 2, from a patient with diffuse large B‐cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high‐resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT 1 regions. We also demonstrated a loss of heterozygosity for TP 53 at 17p13 in conjunction with a TP 53 frameshift mutation. Notably, AMU ‐ ML 2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC ‐sh RNA ‐mediated knockdown. Furthermore, genes involved in cyclin D, mTOR , and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU ‐ ML 2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities.

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

“…Recently, a novel cell line, named AMU-ML2, characterized by the occurrence of a homogeneously staining region at the 8q24 locus and containing more than 20 copies of the entire MYC and PVT1 genes, has been established from a DLBCL patient at diagnosis. Of note, AMU-ML2 cells expressed elevated levels of MYC, PVT1 and circPVT1 and were resistant to vincristine, suggesting a potential link between PVT1 and drug resistance in DLBCL [64]. This hypothesis is in line with previous reports on PVT1-mediated resistance to cisplatin in gastric and ovarian cancers [87].…”

“…No transforming ability of PVT1 and circPVT1 per se has been demonstrated in hematopoietic cells so far, suggesting a role in tumor progression and in support of a proliferative phenotype, rather than in cancer development. Moreover, some new insights on the role of PVT1 in drug response are emerging, including the elevated expression of both PVT1 and circPVT1 in the vincristine-resistant AMU-ML2 DLBCL line [64] and the glucocorticoid-resistant phenotype promoted by circPVT1 in MM models, that is rescued by knockdown [70]. Although some of these data need to be substantiated by scientific publications, they provide a clear path to go in hemato-oncology, where targeting of PVT1 and/or circPVT1 may a be a valuable option for combination therapies.…”

Long Non-coding RNA Expression Profiling Identifies a Four-Long Non-coding RNA Prognostic Signature for Isocitrate Dehydrogenase Mutant Glioma

“…Knockdown of PVT1 inhibited cell proliferation and arrested cell cycle at G1 stage via recruiting EZH2 (zeste homolog 2) and regulating p15 and p16 epigenetically (28). Moreover, some new insights on the role of PVT1 in drug response are emerging, including the elevated expression of PVT1 in the vincristine-resistant AMU-ML2 DLBCL line (48). Recently, the research performed by Li et al confirmed that the downregulated expression of H19 increased the efficacy of temozolomide (TMZ) chemotherapy in glioblastoma multiforme (GBM) cells (49).…”

Clinical Features and Prognostic Impact of Coexpression Modules Constructed by WGCNA for Diffuse Large B‐Cell Lymphoma

“…As a heterogeneous disease, DLBCL can be classified into activated B-cell, germinal center B-cell, and primary mediastinal B-cell subtypes based on gene expression profiling [21]. Though about 70% of DLBCL patients have survival time longer than five years when treated with immunochemotherapy involving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) [22], however, the remaining patients are still dying of this malignant tumor. In addition, the short-and long-term toxicity of chemotherapy, including secondary malignancies and leukemia, adversely affects the long-term prognosis of patients.…”