Anticancer Drug‐mediated Induction of Multidrug Resistance‐associated Genes and Protein Kinase C Isozymes in the T‐Lymphoblastoid Cell Line CCRF‐CEM and in Blasts from Patients with Acute Lymphoblastic Leukemias

Beck, James F.; Brügger, Dorothee; Brischwein, Klaus; Liu, Chao; Bader, Peter; Niethammer, D.; Gekeler, Volker

doi:10.1111/j.1349-7006.2001.tb01178.x

Cited by 20 publications

(11 citation statements)

References 31 publications

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“…on May 10, 2018. by guest www.bloodjournal.org From DNR [71][72][73] and ASP. [74][75][76] To address the possibility that the genes mediating acquired drug resistance might also be active in IF patients, we developed Jurkat and Sup T1 T-ALL cell lines, each with resistance to DNR and ASP, but also to VCR and PRED, as in the case of DNR-resistant Jurkat cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Winter

Jiang²,

Khawaja

et al. 2007

Blood

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The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF IntroductionAcute lymphoblastic leukemia (ALL) is the most common form of cancer among children and young adults. Approximately 15% of patients express cellular and molecular features that are unique to T-lineage acute lymphoblastic leukemia (T-ALL). [1][2][3][4] Through the use of increasingly dose-intensive therapy, combined with an improved understanding of leukemic pathogenesis, disease-free survival for children with ALL has improved over the past 3 decades. 5 However, when matched for NCI-designated clinical risk features of age, initial white blood cell count, and evidence of extramedullary disease, patients with T-ALL are at an increased risk of relapse compared with children treated for precursor B-lineage acute lymphoblastic leukemia (B-ALL). 6 In addition, unlike many of the genetic biomarkers observed in patients with precursor B-ALL, the recurring karyotypic aberrations identified in T-ALL do not consistently correlate with outcome on modern treatment schemas. 2,7,8 For these reasons, the identification of prognostically relevant karyotypic and clinicopathologic abnormalities in T-ALL has been difficult to elucidate. The recent identification of T-ALL risk groups, as defined by minimal residual disease (MRD) status, 6,9,10 activating NOTCH1 mutations, 11-13 and response to induction therapy, 6,14,15 can be used to stratify treatment approaches. Nevertheless, the mechanisms of drug resistance that result in persistent disease and early treatment failure remain poorly understood.Gene expression microarrays are spotted with thousands of 25mer oligonucleotides, which correspond to transcripts of known and hypothetical genes within the human genome. By using microarrays for class discovery in hematopoietic malignancies, it has been possible to identify novel pathways in malignant transformation, 16,17 explore heterogeneities among study populations, 18-21 and segregate patients into prognostically relevant subsets. 18,22 While numerous genes and genetic signatures predicting disease course have been identified for patients with acute myelogenous leukemia, precursor B-ALL, and...

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Section: Discussionmentioning

confidence: 99%

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Winter

Jiang²,

Khawaja

et al. 2007

Blood

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“…MDR1 transcriptional induction typically shows a time and concentration dependence, peaking anywhere between 8-72 h after xenobiotic exposure in most cells, including the CCRF-CEM cells. [37][38][39][40] For these cells, long-term drug exposure is required to overcome translational block and to express P-gp on their surface. 41 Consequently, considering the time frames used in this manuscript (2-4 h co-culture periods), it is more likely that we are observing exogenous P-gp being transferred to the parental cells through MPs rather than induction of transcription, translation and subsequent trafficking to the plasma membrane from intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells

et al. 2009

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Multidrug resistance (MDR), a significant impediment to the successful treatment of cancer clinically, has been attributed to the overexpression of P-glycoprotein (P-gp), a plasma membrane multidrug efflux transporter. P-gp maintains sublethal intracellular drug concentrations by virtue of its drug efflux capacity. The cellular regulation of P-gp expression is currently known to occur at either pre-or post-transcriptional levels. In this study, we identify a 'non-genetic' mechanism whereby microparticles (MPs) serve as vectors in the acquisition and spread of MDR. MPs isolated from drug-resistant cancer cells (VLB 100 ) were co-cultured with drug sensitive cells (CCRF-CEM) over a 4 h period to allow for MP binding and P-gp transfer. Presence of P-gp on MPs was established using flow cytometry (FCM) and western blotting. Whole-cell drug accumulation assays using rhodamine 123 and daunorubicin (DNR) were carried out to validate the transfer of functional P-gp after co-culture. We establish that MPs shed in vitro from drug-resistant cancer cells incorporate cell surface P-gp from their donor cells, effectively bind to drug-sensitive recipient cells and transfer functional P-gp to the latter. These findings serve to substantially advance our understanding of the molecular basis for the emergence of MDR in cancer clinically and lead to new treatment strategies which target and inhibit MP mediated transfer of P-gp during the course of treatment.

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“…Similarly, an association between the expression of MRP1 and the Nmyc oncogen has been firmly established in neuroblastoma [114,119]. Increased MRP1 expression was observed after chemotherapy in relapsed SCLC [73], bladder carcinomas [158], and acute lymphoblastic leukemia (ALL) [11]. Whether this is a consequence of repopulation of drugresistant cells (selection) or upregulation of expression in response to drug exposure (induction) remains to be established.…”

Section: The Pathophysiological Aspect Of Mrp1mentioning

confidence: 99%

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

Bakos

Homolya

2006

Pflugers Arch - Eur J Physiol

153

104

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MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substratebinding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.

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Anticancer Drug‐mediated Induction of Multidrug Resistance‐associated Genes and Protein Kinase C Isozymes in the T‐Lymphoblastoid Cell Line CCRF‐CEM and in Blasts from Patients with Acute Lymphoblastic Leukemias

Cited by 20 publications

References 31 publications

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

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