Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

Abstract

Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P = 0.013, Wilcoxon signed rank test (paired samples); P = 0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G 8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation. Leukemia (2000) 14, 1606-1613.

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

“…5,39 Cytochrome c forms an active complex with APAF-1, which recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] The BAX/APAF-1/Caspase pathway of apoptosis may also be functional in death receptor triggered apoptotic cell death. This process presumably involves a Bid-dependent pathway leading to a conformational change in BAX.…”

“…5 Cytochrome c forms an active complex with APAF-1 that recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] We have shown previously that loss of BAX expression correlates with a poor prognosis in patients with hepatic metastases of colorectal cancer undergoing surgical resection of liver metastases. 13 Similar data were obtained in diffuse aggressive nonHodgkin-lymphoma, 14 ovarian, 15 pancreatic 16 and esophageal cancer 17 where reduced BAX expression was also observed to be a negative prognostic factor.…”

“…Furthermore, we demonstrated that the restoration of BAX expression in breast cancer cell lines resulted in an increased sensitivity to DNA damaging agents. 18 Loss of Bax was associated with relapse and defective activation of caspase-3 in childhood acute lymphoblastic leukemia 11 and drug-specific resistance profiles in chronic lymphocytic leukemia. 19 No data are available, however, on the prognostic significance of loss of BAX in relation to the p53 status in primary colorectal cancer.…”

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

“…Several studies have investigated the predictive value of the expression level of various Bcl-2 family members in ALL at diagnosis. [35][36][37][38][39][40][41][42][43][44][45] The majority of these studies indicate that steady-state levels of individual Bcl-2 family members are not optimal predictors of outcome 35,36,38,39 or ex vivo GC-sensitivity. 37,40,42 On the other hand, several studies using cell viability assays have demonstrated that ex vivo GC-sensitivity has a predictive value in relation to the short-term response to systemic GC monotherapy and to the long-term clinical outcome in response to combination chemotherapy.…”

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…127 Other possible causes include the deregulation of the mitochondrial apoptosome, 67 especially the members of the Bcl-2 family which may show considerable intra-and interdisease variability, eg in lymphoma, 128 and may shift to an apoptosis-refractory profile when resistance develops. 129 Recently, an IAP-neutralizing and therefore apoptosis-promoting mitochondrial protein, termed Leukemia Smac/Diablo, has been identified that obviously plays a critical role in antagonizing the caspase-inhibitory effect of IAPs. 130,131 The role of Smac in tumor biology is as yet unclear but inactivation of this novel player could also result in a resistant phenotype.…”