title: Hematopoietic malignancies demonstrate loss-of-function mutations of BAX.
abstract: The BCL-2 gene family regulates the susceptibility to apoptotic cell death in many cell types during embryonic development and normal tissue homeostasis. Deregulated expression of anti-apoptotic BCL-2 can be a primary aberration that promotes malignancy and also confers resistance to chemotherapeutic agents. Recently, studies of Bax-deficient mice have indicated that the pro-apoptotic BAX molecule can function as a tumor suppressor. Consequently, we examined human hematopoietic malignancies and found that approximately 21% of lines possessed mutations in BAX, perhaps most commonly in the acute lymphoblastic leukemia subset. Approximately half were nucleotide insertions or deletions within a deoxyguanosine (G8) tract, resulting in a proximal frame shift and loss of immunodetectable BAX protein. Other BAX mutants bore single amino acid substitutions within BH1 or BH3 domains, demonstrated altered patterns of protein dimerization, and had lost death-promoting activity. Thus, mutations in the pro-apoptotic molecule BAX that confer resistance to apoptosis are also found in malignancies.
authors.affiliation: Department of Hematology, University Hospital "St. Radboud" Nijmegen, Nijmegen, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: E J
authors.initials: EJ
authors.lastname: Mensink
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: T W
authors.initials: TW
authors.lastname: Sedlak
authors.forename: A W
authors.initials: AW
authors.lastname: Slöetjes
authors.forename: T
authors.initials: T
authors.lastname: de Witte
authors.forename: G
authors.initials: G
authors.lastname: Waksman
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein