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.


Available from: Martin Stanulla
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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. Die Wirksamkeit der antileukämischen Chemotherapie wird durch die Aktivierbarkeit des Signalweges des Tumorsuppressors p53 bestimmt. Im Rahmen der Dissertation wurde der Einfluss mitochondrialer Faktoren auf den p53-Signalweg untersucht. Die Ergebnisse wiesen daraufhin, dass die p53-Aktivierbarkeit an den mitochondrialen Aktivitätszustand und die Bildung von reaktiven Sauerstoffspezies gekoppelt ist, wodurch die erhöhte Chemoresistenz von Zellen in einem ruhenden Zustand erklärt werden kann. Darüber hinaus konnten bei der Evaluierung der experimentellen Ergebnisse an unabhängigen Patientenkohorten neue potentielle Resistenzfaktoren identifiziert werden. Diesbezüglich zeigte sich die Expression des Adhäsionsmoleküls CD11b (ITGAM) von prognostischer Bedeutung und war mit einem ungünstigen Therapieansprechen assoziiert. Die präsentierten Ergebnisse tragen zum grundlegenden Verständnis der molekularen und zellbiologischen Eigenschaften therapieresistenter Leukämiezellen bei und könnten einen Ausgangspunkt für individualisierte Therapiestrategien bei der pädiatrischen ALL darstellen. In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic cells during therapy (minimal residual disease, MRD) is of crucial prognostic significance. From a biological point of view MRD cells are the tumor cells, which survived anti-leukemic therapy. Therefore, the cell biologic characterization of these rare cells may considerably contribute to the identification of cellular and molecular determinants of therapy resistance in ALL. In order to approach this issue experimentally, a procedure has been established, which enabled a gene expression profiling of MRD cells persisting after one week of induction glucocorticoid therapy. The expression changes indicated a shift towards mature B cells, inhibition of cell cycling, and an increase of expression of adhesion (CD11b/ITGAM) and cytokine (CD119/IFNGR1) receptors. The differentiation shift and low proliferative activity in MRD cells has been confirmed by direct comparison with normal B cells at cellular and protein levels. Given that normal B cells are largely therapy resistant, the differentiation shift and low proliferative activity may account for the persistence of blasts during therapy and affect their sensitivity to further therapeutic treatment. Evaluation of the gene expression data in a clinical context indicated a prognostic significance of the CD11b-receptor. The expression of CD11b was inversely correlated with cytoreduction rates measured at clinically important timepoints of induction therapy. Moreover, due to the consistently increased expression levels in leukemic cells under therapy and to the cell surface allocation, CD11b has a promising potential as an MRD-specific marker to improve sensitivity and specificity of flow cytometric MRD detection. With regard to chemotherapy-specific mechanisms of action, activation of the tumor suppressor p53-signaling pathway has been reported in response to a large variety of drugs. The p53 system is highly stress-sensitive and integrates diverse intracellular signals in a complex and poorly defined manner. In this work, the role of mitochondrial activity has been investigated as one of the critical intracellular determinants involved in the regulation of energy metabolism, cellular redox state and apoptosis. 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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    ABSTRACT: This review summarizes recent advances in the application of minimal residual disease (MRD) testing in childhood acute lymphoblastic leukemia (ALL). Polymerase chain reaction amplification of antigen receptor genes, one of the two main methods to study MRD in ALL, could be made more rapid, sensitive and informative by the application of next-generation sequencing technologies. Advances in flow cytometric detection of MRD, the other main method, include the identification of new immunophenotypic markers to recognize ALL cells, the development of computerized approaches to automate data analysis, and the generation of instruments that can rapidly screen large number of cells for immunophenotypic abnormalities while visualizing their morphology. Recent data further corroborate the prognostic value of MRD at early time points during therapy, demonstrate the prognostic significance of MRD among ALL subtypes, and indicate that presenting features can complement the prognostic utility of MRD. MRD is replacing morphology to measure treatment response in ALL and is being used, with promising results, for risk-stratification in clinical protocols. Recent studies provide further evidence of its prognostic significance and point to possible strategies to increase the reliability, applicability and sensitivity of MRD testing.
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