Hematopoietic Malignancies Demonstrate Loss-of-Function Mutations ofBAX

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 ofBax-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.

Regulation of tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in Burkitt's lymphoma cell lines

“…Although Gutierrez et al (1999) suggested that defects in Bax might contribute to FAS resistance in BL, and we and others have identified Bax mutations in BL cell lines (Brimmell et al, 1998;Meijerink et al, 1998;Gutierrez et al, 1999), the expression of Bax and other Bcl-2 family proteins did not correlate with TRAIL sensitivity (Spender et al, 1999). Other potential mechanisms of resistance that might account for TRAIL resistance include altered expression of other regulatory molecules, such as death-associated protein 3 (DAP3) (Miyazaki & Reed, 2001).…”

Bax Induction Activates Apoptotic Cascade via Mitochondrial Cytochrome c Release and Bax Overexpression Enhances Apoptosis Induced by Chemotherapeutic Agents in DLD‐1 Colon Cancer Cells

“…It has been reported that Bax induction alone induces apoptosis in Jurkat cells, 5) but Jurkat cells have a Bax gene mutation and do not express Bax protein. 6) Cancer cells express different levels of proapoptotic Bax protein. 6) The present study demonstrated that Bax induction alone initiated cytochrome c release from mitochondria, activation of caspase 3 and apoptosis to some extent in DLD-1 cells, which originally express a high level of proapoptotic Bax protein.…”

“…6) Cancer cells express different levels of proapoptotic Bax protein. 6) The present study demonstrated that Bax induction alone initiated cytochrome c release from mitochondria, activation of caspase 3 and apoptosis to some extent in DLD-1 cells, which originally express a high level of proapoptotic Bax protein. Recently, a pathway between Bax induction and caspase-3 activation has been reported.…”

“…It has been reported that Bax induction alone induces apoptosis in Jurkat cells, 5) which have a Bax gene mutation. 6) Strobel et al have reported that Bax overexpression enhances apoptosis induced by paclitaxel, vincristine and doxorubicin, but not by carboplatin, etoposide or hydroxyurea in ovarian cancer cells. 7) Wagener et al have reported that Bax induction alone does not induce apoptosis of breast cancer cells, but sensitizes the cells to epirubicin-induced apoptosis.…”

DNA Damage‐Induced Programmed Cell Death: Potential Roles in Germ Cell Development

“…Bax is often mutated in human colorectal and hematopoietic malignancies. 41,42 In mice, loss of Bax promotes tumor formation. 43 Bax has also been shown to have a role in DNA damage-induced PCD.…”