Markers of apoptosis and proliferation related gene products as predictors of treatment outcome in childhood acute lymphoblastic leukemia

Abstract

The aim of the study is to characterize markers of apoptosis in children with acute lymphoblastic leukemia (ALL) in relation to treatment outcome of the disease. The study was performed on 34 children with ALL and 39 healthy children as a control group. Apoptosis was assessed by cell morphology; DNA fragmentation; ELISA and RT-PCR for CD95, CD95L, BcL-2 and nuclear factor-kappa B (NF-kappaB); and flow cytometry for CD95, CD40, CD49d and CD11a. Apoptosis was significantly lower in patients than controls. Apoptosis detected by CD95 ligand was significantly lower in cases with no remission after treatment than those who achieved remission. Anti-apoptotic factors: CD40, BcL-2, and NF-kappaB were all found to be higher in cases than controls and in cases with no remission than those achieved remission. CD49d was significantly lower in cases than controls, and significantly lower in cases with who did not achieve remission. CD11a levels were similar in the various groups. Delayed apoptosis of ALL cells is genetically controlled either directly or indirectly by a network of oncogenes and tumor suppressor genes. CD40 appeared to stimulate both T and B lineage and is considered the most potent influencer and predictor of resistance to therapy. Inhibitors for the activity of CD40, Bcl-2 and NF-kappaB as well as stimulants to CD95 could have a potential therapeutic benefit.

Monitoring treatment response of childhood acute lymphocytic leukemia with certain molecular and biochemical markers

“…In accordance with our results, Hafez et al [21] demonstrated that apoptosis was lower in patients than in controls and suggested that inhibitors for the activity of Bcl-2 and NF-κB as well as stimulants to CD 95 could have a potential therapeutic benefit. Consistent with our results, Tamiya et al [22] found defects in expression of Fas antigen on leukemia cells because of mutations in Fas genes of these cells.…”

Inhibition of NF-kappa B can enhance Fas-mediated apoptosis in leukemia cell line HL-60

“…Studies in recent years indicate that continuous abnormal activation of NF-κB exists in various types of leukemia cells, while it has a relationship with Fas-mediated apoptosis resistance in leukemia cells [3][4][5]. NF-κB is considered to be a predictor of poor treatment outcome in childhood acute lymphoblastic leukemia, and inhibitors for the activity of NF-κB and stimulants to Fas could have a potential therapeutic benefit [6]. Many researches indicate that the sensitivity of tumor cells, such as the lymphoma cell line HuT78 and T cell line H9, to apoptosis can be enhanced by inhibiting NF-κB, but the mechanism is not clear yet [7][8][9].…”

Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2–mediated resistance

“…High Bcl-2 levels and a decrease of the Bax/Bcl-2 ratio have been associated with poor prognosis in childhood ALL in some studies. 31,32 We therefore investigated the effect of XIAP inhibitors on TRAIL-induced apoptosis in Jurkat leukemia cells with ectopic expression of Bcl-2 ( Figure 5A). Bcl-2 overexpression almost completely inhibited TRAIL-induced apoptosis (Figure 5B), consistent with the idea that type II Jurkat cells depend on the mitochondrial pathway for TRAIL-induced apoptosis.…”