CD11b is a therapy resistance- and minimal residual disease-specific marker in precursor B-cell acute lymphoblastic leukemia

Experimental and Clinical Research Center, Charité Medical School, 13125 Berlin, Germany.
Blood (Impact Factor: 10.45). 03/2010; 115(18):3763-71. DOI: 10.1182/blood-2009-10-247585
Source: PubMed


A consistently increased mRNA expression of the adhesion receptor CD11b is a hallmark of the reported genomewide gene expression changes in precursor B-cell acute lymphoblastic leukemia (PBC-ALL) after 1 week of induction therapy. To investigate its clinical relevance, CD11b protein expression in leukemic blasts has been prospectively measured at diagnosis (159 patients) and during therapy (53 patients). The initially heterogeneous expression of CD11b inversely correlated with cytoreduction rates measured at clinically significant time points of induction therapy in the ALL-Berlin-Frankfurt-Münster 2000 protocol. CD11b positivity conferred a 5-fold increased risk of minimal residual disease (MRD) after induction therapy (day 33) and of high-risk group assignment after consolidation therapy (day 78). In the multivariate analysis CD11b expression was an independent prognostic factor compared with other clinically relevant parameters at diagnosis. During therapy, CD11b expression increased early in most ALL cases and remained consistently increased during induction/consolidation therapy. In more than 30% of MRD-positive cases, the CD11b expression on blast cells exceeded that of mature memory B cells and improved the discrimination of residual leukemic cells from regenerating bone marrow. Taken together, CD11b expression has considerable implications for prognosis, treatment response monitoring, and MRD detection in childhood PBC-ALL.

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    ABSTRACT: Bei der kindlichen akuten lymphoblastischen Leukämie (ALL) ist die Persistenz der leukämischen Zellen unter der Therapie (minimale Resterkrankung, MRD) von entscheidender prognostischer Bedeutung. Um Determinanten der Therapieresistenz bei der ALL zu identifizieren, wurden MRD-Zellen mittels genomweiter Genexpressionsanalyse eingehend charakterisiert. Die bioinformatische Auswertung der Genexpressionsdaten deutete daraufhin, dass sich die persistierenden Blasten in Richtung ruhender reifer B-Zellen entwickelt haben. Die Differenzierung der MRD-Zellen und ihre verringerte proliferative Aktivität konnte durch den Vergleich mit normalen B-Zellen auf zellulärer Ebene und Proteinebene bestätigt werden. Der ruhende, reifere Zustand der MRD-Zellen könnte die Therapieresistenz erklären und Auswirkungen auf den weiteren Verlauf der Chemotherapie haben, die in erster Linie auf proliferierende Zellen abzielt. 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Using cellular systems with endogenously expressed wild-type p53, including ALL blasts and normal lymphocytes, a linkage between mitochondrial activity and cellular stress responsiveness upstream of p53 activation could be identified. Through this linkage, resting cells with a downregulated mitochondrial activity have been found to acquire stress- and chemoresistance at p53 level. The presented data offer new insights into the mechanisms of therapy resistance and sensitivity of leukemic blasts. The identified parameters may be useful in predicting MRD status and clinical outcome after induction therapy and potentially provide a part for a future basis for more individually designed treatment strategies in upcoming clinical trials.
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