Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome

Abstract

We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-x L , Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitro resistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…94 The degree of TCD correlates with clinical outcome in several tumor settings. 95,96 Some chemotherapeutics, including anthracyclines, oxaliplatin and CTX, are unique in their capacity to induce an immunogenic type of TCD, 21,97 thereby converting dying tumor cells into adjuvanted-endogenous vaccines. The rational base of vaccination is that tumor antigens must be captured by activated DCs, which would activate CD4 and CD8 T-cell-mediated adaptive immune responses.…”

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

“…[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. [46][47][48][49][50] Therefore, analysis of GC-mediated changes of several Bcl-2 family members might provide an even more reliable predictive assay.…”

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

“…In a clinical trial of childhood ALL reported by Salomons et al, 117 blasts from patients with newly diagnosed childhood ALL were examined for levels of Bcl-2 protein family expression. Expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-xL, Mcl-1) were highly variable in blasts from the 78 children with newly diagnosed ALL tested.…”