Expression of <i>mdr1</i> and mrp in the normal B‐cell homologue of B‐cell chronic lymphocytic leukaemia

Wall, Dominic; El-Osta, Sam; Tzelepis, D; Bertoncello, Ivan; Kantharidis, Phillip; Chou, Sawako; Zalcberg, John; Parkin, John

doi:10.1046/j.1365-2141.1997.d01-2090.x

Cited by 10 publications

(7 citation statements)

References 56 publications

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“…In B-CLL, P-glycoprotein expression is felt to be intrinsic rather than acquired, reflecting different basal levels of MDR1 expression in the different lymphocyte subsets [16,28,29]. Some of this intrinsic expression may vary as a result of differential influences of hormone levels on the developing lymphocyte, and in this regard it is interesting that some have shown that gonadal hormones have a profound effect on lymphopoiesis [31].…”

Section: Discussionmentioning

confidence: 99%

“…Of note is a recent study which found that the normal homologue of the B-type CLL cell, a tonsillar lymphocyte, expresses Pgp [29]. In these studies, expression of MDR1 was demonstrated using many techniques, including RNA analysis with slot blotting or RT-PCR, flow cytometry using different monoclonal antibodies, and functional studies of dye efflux, usually using rhodamine-123.…”

Section: Introductionmentioning

confidence: 97%

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Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity

Steiner

Polliack

Kimchi-Sarfaty

et al. 1998

Annals of Hematology

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Peripheral blood samples from 61 patients (36 male, 25 female) with all stages of B-type chronic lymphocytic leukemia (CLL) were studied for MDR1 phenotype using monoclonal antibodies and rhodamine-123 dye exclusion, a functional assay of MDR1 expression. The duration of the disease varied from 1 month to 22 years at the time of initial study. Overall, 74% of the patients were positive for rhodamine-123 exclusion. When analyzed by gender, significantly more men than women were positive (89% versus 48%, p<0.001). There were more positive men than women for every stage of the disease. Female patients were found to be either MDR1 phenotype positive or negative at any stage of the disease. In contrast, all male patients with early (stages 0-II) disease were MDR1 phenotype positive. One early-stage (stage II) male patient converted from rhodamine-efflux positive to rhodamine-efflux negative as he progressed from stage-II to stage-IV disease. We suggest that some of the differences in disease biology of male versus female CLL patients (women having a more benign course) may be due to gender-dependent differences in drug-resistance gene activity, including MDR1. Our results also emphasize the need to take into account gender in evaluating the clinical course of patients with CLL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity

Steiner

Polliack

Kimchi-Sarfaty

et al. 1998

Annals of Hematology

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“…Reverse transcription (RT) was performed with a first-strand cDNA kit following the protocol recommended by the manufacturer (Life Technologies). (61). The cycling parameters consisted of 95°C for 60 s, followed by 32 cycles at 95°C for 60 s, 58°C for 60 s, and 72°C for 60 s and 1 cycle at 72°C for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Precipitous Release of Methyl-CpG Binding Protein 2 and Histone Deacetylase 1 from the Methylated Human Multidrug Resistance Gene (MDR1) on Activation

El‐Osta

Kantharidis

Zalcberg

et al. 2002

Molecular and Cellular Biology

172

139

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Overexpression of the human multidrug resistance gene 1 (MDR1) is a negative prognostic factor in leukemia. Despite intense efforts to characterize the gene at the molecular level, little is known about the genetic events that switch on gene expression in P-glycoprotein-negative cells. Recent studies have shown that the transcriptional competence of MDR1 is often closely associated with DNA methylation. Chromatin remodeling and modification targeted by the recognition of methylated DNA provide a dominant mechanism for transcriptional repression. Consistent with this epigenetic model, interference with DNA methyltransferase and histone deacetylase activity alone or in combination can reactivate silent genes. In the present study, we used chromatin immunoprecipitation to monitor the molecular events involved in the activation and repression of MDR1. Tumors become resistant to chemotherapy by a variety of mechanisms, including altered DNA repair, alterations in scavenging enzymes, and increased drug efflux. Although clinical drug resistance may be multifactorial, understanding these various mechanisms is important and may afford a means of improving treatment regimens. One of the most extensively studied mechanisms of multidrug resistance is associated with the overexpression of the MDR1 product, P glycoprotein (Pgp) (for reviews see references 27 and 55). A transmembrane protein, Pgp acts as an efflux pump, reducing intracellular drug levels and thus cytotoxic activity. We and others have demonstrated that the human MDR1 promoter is activated by changes in CpG methylation in B-cell chronic lymphocytic leukemia (26), acute myeloid leukemia (38), and tumor cell lines (12).DNA hypermethylation is associated with transcriptional silencing and is accompanied by the accumulation of deacetylated histones on heterochromatin (13,21). Methylation is often associated with the pathological silencing of tumor suppressor genes in human cancer and neurodevelopmental syndrome (20, 23). In contrast, transcriptionally active chromatin is characterized by the enrichment of hyperacetylated histone and is generally associated with hypomethylated chromatin (2, 34). The mechanisms underlying the correlation between DNA methylation and histone deacetylation in the control of gene expression have been established by recent biochemical experiments (24,42). Evidence has emerged that a family of methylCpG binding proteins binds heterochromatin to stably repress transcription (10, 18). The transcriptional repressor methylCpG binding protein 2 (MeCP2 ) is the best-characterized family member (18,41). MeCP2 is typically associated on heterochromatin in a methylation-dependent manner by its methyl-binding domain (MBD) and can displace histone H1 for nucleosome binding, indicating that it can dynamically interact with assembled chromatin (30,40). The transcriptional-repression domain of MeCP2 recruits the corepressors mSin3 and histone deacetylases (HDACs) (24, 42), causing transcriptional repression (41). Moreover, repression by MeCP2 is partial...

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“…However, an MDR + phenotype in CLL does not appear to correlate with either staging and clinical parameters (66,72), and/or in vivo or in vitro sensitivity to drugs (73). Expression of p-glycoproteins has been documented in CD19 + CD5 + B cells from tonsils and blood in normal individuals (71,74), and it has been suggested that p-glycoprotein expression may be an inherent characteristic of CLL cells.…”

Section: Multidrug Resistance Phenotypementioning

confidence: 99%

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

Matutes

Polliack²

2000

Rev Clin Exp Hematol

108

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In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.

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Expression of mdr1 and mrp in the normal B‐cell homologue of B‐cell chronic lymphocytic leukaemia

Cited by 10 publications

References 56 publications

Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity

Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity

Precipitous Release of Methyl-CpG Binding Protein 2 and Histone Deacetylase 1 from the Methylated Human Multidrug Resistance Gene (MDR1) on Activation

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

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