Open AccessOverexpression of B‐cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response
Author(s) -
Tahara Kenichi,
Takizawa Makiko,
Yamane Arito,
Osaki Yohei,
Ishizaki Takuma,
Mitsui Takeki,
Yokohama Akihiko,
Saitoh Takayuki,
Tsukamoto Norifumi,
Matsumoto Morio,
Murakami Hirokazu,
Nojima Yoshihisa,
Handa Hiroshi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13283
Subject(s) - downregulation and upregulation , microbiology and biotechnology , plasma cell , biology , cell culture , dna damage , gene expression , cytidine deaminase , transfection , germinal center , b cell , cancer research , gene , antibody , immunology , dna , genetics
B‐cell lymphoma 6 ( BCL 6) attenuates DNA damage response ( DDR ) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center ( GC ) B cells. Although BCL 6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL 6 in primary multiple myeloma ( MM ) cells. However, the functional roles of BCL 6 in MM cells are largely unknown. Here, we report that overexpression of BCL 6 in a MM cell line, KMS 12 PE , induced transcriptional repression of ataxia telangiectasia mutated ( ATM ), a DDR signaling kinase, which was associated with a reduction in γH2 AX formation after DNA damage. In contrast, transcription of known targets of BCL 6 in GC B cells was not affected, suggesting a cell type‐specific function of BCL 6. To further investigate the effects of BCL 6 overexpression on the MM cell line, we undertook mRNA sequence analysis and found an upregulation in the genomic mutator activation‐induced cytidine deaminase ( AID ) with alteration in the gene expression profile, which is suggestive of de‐differentiation from plasma cells. Moreover, interleukin‐6 exposure to KMS 12 PE led to upregulation of BCL 6 and AID , downregulation of ATM , and attenuation of DDR , which were consistent with the effects of BCL 6 overexpression in this MM cell line. Taken together, these results indicated that overexpression of BCL 6 alters gene expression profile and confers decreased DDR in MM cells. This phenotypic change could be reproduced by interleukin‐6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells.