Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia

Abstract

Molecular parameters involved in the prediction of response of childhood acute lymphoblastic leukemia (ALL) are still unclear. We have evaluated the expression and mutational status of p53 and the expression of bcl-x(L) and bax in a series of 62 consecutive children (median age: 4 years; 38 males and 24 females) affected by de novo ALL. Alterations and overexpression of p53 were uncommon events (9/62, 14.5%) while bcl-x(L) and bax overexpression were frequent (about 70%). EFS was directly correlated to age<6 years (p=0.0178), nonT phenotype (p=0.0470), WBC at diagnosis<or=20000/microl (p=0.0093), response to induction therapy with prednisone (p=0.0211) and inversely correlated to mutated p53 or overexpression of p53 (p=0.0039) and high intensity of Bcl-xL expression (p=0.0055). OS was directly correlated with age<6 years (p=0.0004), female gender (p=0.0139), nonT phenotype (p=0.0012), WBC at diagnosis<or=20000/microl (p=0.0187), response to induction therapy with prednisone (p=0.0211), wild type p53 or low expression of p53 (p=0.035). When all factors were considered in a stepwise Cox regression analysis, only the good response to PDN (p=0.013) and the low intensity of Bcl-xL expression (p=0.001) were independent significant prognostic factors with regard to EFS. Moreover, only age (p=0.022), gender (p=0.036) and WBC at the diagnosis (p=0.050) were independent prognostic factors with regard to OS. Moreover, the mutated status of p53 was statistically correlated to the resistance to the induction therapy with PDN (correlation coefficient: -0.349, p=0.008). In conclusion, both bcl-xL and bax were frequently expressed at high intensity, but only bcl-xL was an independent predictor of EFS in our series. Moreover, p53 alterations were uncommon and alone not strong independent predictors of outcome, but they were correlated to poor response to therapy with PDN and inversely correlated to EFS and OS in univariate analysis.

Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo

“…Instead, ABT-737 binds to multidomain antiapoptotic Bcl-2 family proteins, preventing them from sequestering proapoptotic BH3-only proteins. 18,19 Overexpression of antiapoptotic Bcl-2 (Bcl-2 and Bcl-X L ) family proteins has been observed in acute myeloid leukemia (AML), [20][21][22] ALL, 23,24 and other cancers. 24,25 Bcl-X L overexpression has been reported as an independent predictor of poor event-free survival (EFS) in pediatric ALL.…”

“…24,25 Bcl-X L overexpression has been reported as an independent predictor of poor event-free survival (EFS) in pediatric ALL. 23 Effective pharmacologic inhibition of the Bcl-2 family of proteins could lower the apoptotic threshold in leukemia cells, resulting in synergy with other chemotherapeutic agents, including drugs commonly used for remission induction in primary and relapsed leukemia, such as vincristine, glucocorticoids, and L-ASP.…”

“…24,25 Bcl-X L overexpression has been reported as an independent predictor of poor event-free survival (EFS) in pediatric ALL. 23 Effective pharmacologic inhibition of the Bcl-2 family of proteins could lower the apoptotic threshold in leukemia cells, resulting in synergy with other chemotherapeutic agents, including drugs commonly used for remission induction in primary and relapsed leukemia, such as vincristine, glucocorticoids, and L-ASP.Using both in vitro and in vivo models of ALL, we investigated the potential for synergistic activity of ABT-737 in combination with vincristine, L-ASP, and dexamethasone (VXL), drugs commonly used in both induction and reinduction therapy for ALL. As For personal use only.…”

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.…”

Homoharringtonine acts synergistically with SG235-TRAIL, a conditionally replicating adenovirus, in human leukemia cell lines

“…HHT induces apoptosis in myeloid leukemia cells through affecting caspase-3 and Bax, a pro-apoptotic factor [18][19][20][21] . Overexpression of two antiapoptotic proteins Bcl-2 and Bcl-x L is commonly observed in many cancer types including leukemia, which is associated with chemotherapy resistance [32][33][34] . In addition, Bcl-2 family proteins are critical for the determination of sensitivity to TRAIL [35,36] .…”