BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability.
Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a T-cell leukaemia line), which lacked detectable BAX expression. Apoptosis of DG75 cells induced by low serum or ionomycin was significantly delayed relative to similar Burkitt lymphoma cell lines with normal BAX levels. Although DG75 and Jurkat cells expressed several BAX RNA species including the prototypical BAX alpha RNA, the absence of BAX protein was due to single base deletions and additions in a polyguanine tract within the BAX open reading frame. These frameshift mutations result in premature termination of translation and have recently also been identified in some colon cancers with microsatellite instability. Although mismatch repair defects are not considered a common feature of haemopoietic malignancies, DG75 and Jurkat cells had widespread microsatellite instability and did not express detectable levels of MSH2. In Jurkat cells, lack of MSH2 expression was due to a point mutation in exon 13 of MSH2 resulting in premature termination of translation. Our results suggest that a pathway linking mismatch repair defects, BAX tumour suppressor frameshift mutations and resistance to apoptosis may be a key feature of some lymphomas and leukaemias.
Brimmell
M
M
Ludwig Institute for Cancer Research, Imperial College School of Medicine at St Mary's, London.
Mendiola
R
R
Mangion
J
J
Packham
G
G
D017209:Apoptosis / Q000235:genetics*; D002051:Burkitt Lymphoma; D004268:DNA-Binding Proteins; D016368:Frameshift Mutation / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics*; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm; D051028:bcl-2-Associated X Protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein