Significantly Increased CD70 Up Regulation on TEL-AML Positive B Cell Precursor Acute Lymphoblastic Leukemia Cells Following CD40 Stimulation

Abstract

Background: TEL-AML the most common genetic alteration in childhood precursor B acute lymphoblastic leukemia (BCP-ALL) is associated with a favorable prognosis.

Patients and method: We studied the expression of nerve growth factor/tumor necrosis factor receptor (NGFR/TNFR)/ligand family members on 108 primary BCP-ALL samples by flow cytometry and compared both their baseline expression and CD40-induced modulation on TEL-AML positive and negative leukemia samples.

Results: Our findings demonstrate that TEL-AML positive patients exhibit a significantly higher percentage of CD40, CD27 and p75NTR positive blasts at diagnosis. This might well contribute to the improved relapse-free survival of these patients assessed in Kaplan Meier analysis as CD27 and p75NTR directly mediate apoptotic signals. Furthermore CD40 ligation enhances antigen presenting and T cell stimulatory capacity via significant up regulation of CD70 while adequate response to physiological maturation signals as indicated by concomitant down regulation of CD27 is retained in TEL-AML positive leukemia.

Conclusion: These data provide novel insights in immunological control mechanisms preserved in this leukemia subtype and suggest that not only treatment with chemicals such as HDAC inhibitors but also retained in vivo response to CD40 ligation contributes to improved immune surveillance in these patients which may add to a superior relapse-free survival observed particularly in the presence of other risk factors.

Zusammenfassung

Hintergrund: TEL-AML ist die bei pädiatrischen Patienten mit einer akuten Vorläufer B lymphoblastischen Leukämie (BCP-ALL) am häufigsten nachgewiesene Genveränderung und geht mit einer meist guten Prognose einher.

Patienten und Methode: Wir haben die Expression von Mitgliedern der Nerve growth factor/Tumor necrosis factor Rezeptor (NGFR/TNFR)/Ligand Familie auf 108 primären BCP-ALL Proben mittels Durchflusszytometrie untersucht und sowohl deren basale Expression sowie die CD40-induzierte Modulation auf TEL-AML positiven und negative Proben verglichen.

Ergebnisse: Unsere Ergebnisse zeigen, dass TEL-AML positive Patienten einen signifikant höheren Prozentsatz an CD40, CD27 und p75NTR positiven ALL-Zellen bei Diagnosestellung aufweisen. Dies kann zum besseren rezidiv-freien Überleben, das sich in der Kaplan Meier Analyse bei dieser Patientengruppe zeigt, beitragen, da CD27 und p75NTR bekanntermaßen direkt Apoptosepathways aktivieren können. Zusätzlich verbessert die CD40 Ligation zum einen die Antigenpräsentation und T Zellstimulation durch signifikante Hochregulation von CD70 auf TEL-AML positiven ALL Zellen und führt auch, ähnlich wie im Rahmen der physiologischen Ausreifung auf normalen B Zellen, zur Herunterregulation von CD27 auf diesen Zellen.

Schlussfolgerung: Diese Ergebnisse unterstüt­zen die These, dass immunologische Kontrollmechanismen, die insbesondere bei TEL-AML positiven Leukämieproben erhalten sind, sich nicht nur wie bereits beschrieben durch den Einsatz von HDAC Inhibitoren verbessern lassen, sondern auch zu einer durch CD40 Ligand vermittelten, T Zell abhängigen Immunkontrolle in vivo beitragen können, welche wiederum zu einem verbesserten rezidiv-freien Überleben vor allem bei Vorliegen anderer Risikofaktoren beitragen kann.

Key words

acute leukemia - TEL-AML rearrangements - TNF receptors - immune response

Schlüsselwörter

akute Leukämie - Tel-AML Rearrangement - TNF Rezeptoren - Immunantwort

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