Reduced expression and defective modulation of TNF receptor/ligand family molecules on proB-ALL blasts.

BACKGROUND: There is a subgroup of pediatric patients with an immature immunophenotype of proB-ALL that still poses a therapeutic challenge, even if the overall prognosis in B cell precursor acute lymphoblasic leukemia (BCP-ALL) is very good. Due to impaired treatment response these patients are prone to suffer relapse and are thus by definition stratified into the clinically defined high risk group receiving intensified chemotherapy. Besides response to chemotherapy long term prognosis is also influenced by immunological control mechanisms. Thus, high expression of the TNF receptor CD40 has been shown to prevent particularly late relapse in BCP-ALL suggesting a pivotal role of this regulatory molecule for maintenance of the remission status.

PATIENTS AND METHODS: We therefore determined the baseline expression and CD40-mediated modulation of TNF receptor and costimulatory molecules in 5 patients with proB-ALL, 8 with preB-ALL and 22 with c-ALL performing FACS analysis. We particularly compared the TNF receptor status on proB-ALL blasts to the expression on more mature preB- and c-ALL blasts.

RESULTS: Here, we demonstrate for the first time a significantly lower baseline expression and CD40-induced modulation capacity of TNF receptor and costimulatory molecules in pediatric proB-ALL compared to more mature precursor B-ALL blasts.

CONCLUSION: The lower expression and defective capacity of proB-ALL blasts to respond to CD40 ligand stimulation might resemble the immature feature of these blasts and besides increased chemoresistance contribute to the impaired prognosis of these patients due to escape from apoptosis and immunological control mechanisms.