BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration

Abstract

Clinical risk factor models such as the International Prognostic Index are used to identify diffuse large B-cell lymphoma (DLB-CL) patients with different risks of death from their diseases. To elucidate the molecular bases for these observed clinical differences in outcome, differential display was used to identify a novel gene, termed BAL (B-aggressivelymphoma), which is expressed at significantly higher levels in fatal high-risk DLB-CLs than in cured low-risk tumors. The major BAL complementary DNA encodes a previously uncharacterized 88-kd nuclear protein with a duplicated N-terminal domain homologous to the nonhistone portion of histone-macroH2A and a C-terminal alpha-helical region with 2 short coiled-coil domains. Of note, the BAL N-terminus and secondary structure resemble those of a recently identified human protein, KIAA1268. In addition, bothBAL and KIAA1268 map to chromosome 3q21, further suggesting that these genes belong to a newly identified family. BAL is expressed at increased levels in DLB-CL cell lines with an activated peripheral B cell, rather than a germinal center B cell, phenotype. This observation and the characteristic dissemination of high risk DLB-CLs prompted studies regarding the role of BAL in B-cell migration. In classical transwell assays, stable BAL-overexpressing B-cell lymphoma transfectants had significantly higher rates of migration than vector-only transfectants, indicating that the risk-related BAL gene promotes malignant B-cell migration.

The macro domain protein family: Structure, functions, and their potential therapeutic implications

“…It is now well established that various members of the macro domain family are overexpressed in a range of human tumors [73][74][75][76][77][78][79][80]. Generally, MACROD1 appears to be the family member most widely overexpressed in human cancers, with high levels of expression observed in endometrial carcinoma, gastric carcinoma, colorectal carcinoma, and breast carcinoma [74][75][76][77][78].…”

“…Important molecular marker correlations are also now beginning to be drawn. Clinical research has indicated that the expression level of some of macro domain proteins in carcinoma is significantly higher than that in matched normal tissues and is correlated significantly with shortened survival in patients with cancer [76][77][78][79]81]. In addition, macro domain proteins could become useful biomarkers to predict the risk of recurrence of some tumors.…”

“…In contrast, knockdown of MACROD1 in prostate cancer cell lines has been shown to decrease the growth of these cells in vitro [65]. Macro domain protein has an important role in enabling cancer cells to adapt their metabolism to cope with the demands of enhanced migration and metastasis, PARP-9, for instance, was found to be overexpressed in aggressive diffuse large B-cell lymphomas (DLB-CL), and its ectopic over-expression promotes the migration of lymphocytes in vitro, which indicates that PARP-9 might promote the dissemination of malignant B cells in high-risk DLB-CL [79]. ALC1 is likely to have key roles in the initiation and progression of HCC, an assertion that is supported by overexpression data for a range of HCC cell lines.…”

Functions of alphavirus nonstructural proteins in RNA replication

“…It usually exists on its own as a small protein, but the human genome also contains open reading frames in which this domain is repeated. A gene termed BAL, which contains a duplicated nsP3-like domain, is a highly expressed risk factor in certain aggressive lymphomas (140). The conservation between viral and cellular homologs is unusually high for an RNA virus protein, reaching up to 35-40% sequence identity (139).…”

Differential Activities of Cellular and Viral Macro Domain Proteins in Binding of ADP-Ribose Metabolites

“…12 Three human genes encode the B-aggressive lymphoma (BAL) family of transcription factors. [13][14][15] BAL proteins include two or three tandem macro domains followed by a poly (ADP-ribose) polymerase (PARP) domain, reinforcing the link of the macro family with ADP-ribose derivatives. The final three human macro domain proteins are poorly understood.…”