Reduced Expression and Defective Modulation of TNF Receptor/Ligand Family Molecules on proB-ALL Blasts

Abstract

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.

Zusammenfassung

Hintergrund: Trotz der insgesamt sehr guten Prognose bei Kindern mit Vorläufer-B-Zellleukämien gibt es eine Untergruppe von Patienten mit unreifem proB-ALL-Phänotyp, da sie ein schlechtes Ansprechen auf die Standardtherapien aufweisen. Diese Patienten werden definitionsgemäß der Hochrisikogruppe zugeordnet und erhalten eine intensivierte Chemotherapie. Das Langzeitüberleben wird jedoch auch durch die Effizienz der immunologischen Kontrolle mitbestimmt. Wir konnten kürzlich zeigen, dass eine hohe Expression des TNF-Rezeptors CD40 insbesondere vor dem Auftreten von späten Rezidiven bei Kindern mit Vorläufer-B-ALL schützt und dieses Molekül somit eine wichtige Rolle bei der Aufrechterhaltung des Remissionsstatus spielt.

Patienten und Methode: Wir haben die Expression und Modulation von TNF-Rezeptor- und kostimulatorischen Molekülen nach CD40-Stimulation auf 5 proB-, 8 präB- und 22 c-ALL-Proben mittels FACS-Analyse untersucht. Dabei haben wir insbesondere den Unterschied zwischen unreifen proB-ALL-Blasten im Vergleich zu den reiferen präB- und c-ALL-Proben ermittelt.

Ergebnis: Wir zeigen hier zum ersten Mal, dass unreife proB-ALL-Blasten eine signifikant niedrigere basale Expression, aber auch CD40-induzierte Modulationsfähigkeit von TNF-Rezeptor und kostimulatorischen Molekülen im Vergleich zu reiferen Vorläufer-B-ALL aufweisen.

Schlussfolgerung: Die niedrigere basale Expression von TNF-Molekülen und die verminderte Fähigkeit der Hochregulation von TNF- und kostimulatorischen Molekülen nach CD40-Stimulation von proB-ALL-Blasten mag Ausdruck des unreifen Immunphänotyps sein und neben der höheren Chemoresistenz eine Erklärung für die schlechtere Prognose dieser Patienten darstellen, da sich die Blasten auf diese Weise Apoptosemechanismen und der Immunkontrolle entziehen können.

TNF receptors - proB-ALL - pediatrics

TNF Rezeptormoleküle - proB-ALL - Pädiatrie

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