Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Martin Stanulla
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article ·
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents principles of diagnosis of acute lymphoblastic leukemia (ALL) according to WHO 2008 classification. In order to establish diagnosis in adults, morphology, immunophenotype, cytogenetics and genetics aberrations (especially t(9;22), t(4;11)) must be done in each case of acute leukemia. Immunophenotype to define minimal residual disease (MRD) should be done before treatment. Monitoring of MRD was postulated as an additional risk criterion and is useful of treatment strategy. PALG ALL treatment's protocol (www.palg.pl) is recommended. The combination of chemotherapy and imatinib should be standard treatment in BCR-ABL positive cases. Bone marrow transplantation is recommended during CR1 in BCR-ABL positive cases and in patients MRD positivity after induction treatment.
    No preview · Article · Jan 2010 · Acta haematologica Polonica
  • [Show abstract] [Hide abstract]
    ABSTRACT: A multitude of clinical and biologic factors have been associated with response to treatment in childhood acute leukemia but their predictive power is far from absolute, and their usefulness for guiding clinical decisions in individual patients is inherently limited. Rather than predicting treatment response, in vivo measurements of leukemia cytoreduction provide direct information on the effectiveness of treatment in each patient. Such estimates, when performed by conventional morphologic techniques, have a relatively low sensitivity and accuracy: in most cases, leukemic cells can be detected in bone marrow with certainty only when they constitute 5% or more of the total cell population. These limitations are overcome by methods for detecting minimal (i.e., submicroscopic) residual disease (MRD), which can be 100 times more sensitive than morphology and allow a more objective assessment of treatment response. The definition of “remission” in patients with acute leukemia by these methods has become the standard at many cancer centers. Initial reservations about the clinical utility of MRD testing arose from concerns regarding the heterogeneous distribution of leukemia during clinical remission. Another concern was that MRD signals may not correspond to viable leukemic cells with the capacity for renewal. Indeed, even contemporary MRD assays cannot determine whether the signals detected originate from stem cells or from more differentiated cells incapable of driving durable cell growth. In view of the strong correlation between MRD levels and relapse, it is now clear that the presence of MRD in most cases directly or indirectly demonstrates the persistence of leukemic cells that are resistant to chemotherapy and are capable of driving the recurrence of leukemia.
    No preview · Article · Jan 2010
Show more