Multidrug resistance mechanisms in chronic lymphocytic leukaemia

Consoli, Ugo; Santonocito, Anna Maria; Stagno, Fabio; Fiumara, Paolo; Privitera, Anna; Parisi, Giuseppe Fabio; Gm, Giustolisi; Pavone, B. G.; Palumbo, Giuseppe A.; Raimondo, Francesco Di; Milone, Giuseppe; Guglielmo, Patrizia; Giustolisi, Rosario

doi:10.1046/j.0007-1048.2002.03344.x

Cited by 37 publications

(20 citation statements)

References 30 publications

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“…23,24, [43][44][45][46] The development of drug resistance is a major clinical problem in CLL. [47][48][49][50][51] Therefore, it is important to note that sensitivity to LC-1 was For personal use only. on May 8, 2018.…”

Section: Discussionmentioning

confidence: 99%

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

Hewamana

Alghazal²,

Lin³

et al. 2008

Blood

143

132

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In this study, we characterized nuclear factor B (NF- B IntroductionB-cell chronic lymphocytic leukemia (CLL) is a malignancy characterized by the accumulation of CD5, CD19, and CD23 positive lymphocytes. Diagnosis is aided by the CLL immunophenotyping score which includes assessment of CD5 and CD23, FMC7, CD79b, and surface IgM. 1 Although CLL is the commonest leukemia in the Western world, it manifests a very heterogeneous clinical course, with some patients having normal age-adjusted survival, whereas the median survival for those patients with advanced stage disease is only 3 years. 2 The factors that contribute to the pathogenesis and progression of this disease are poorly understood, but decreased susceptibility to apoptosis 3 and dysregulated proliferation have been implicated. 4 Clinical studies have shown that high ZAP-70 expression, high CD38 expression, unmutated V H genes, and cytogenetic abnormalities (especially deletions of 11q and 17p) are all associated with a poor prognosis. [5][6][7][8][9] Nuclear factor B (NF-B) is a collective name for a group of inducible homodimeric and heterodimeric transcription factors made up of members of the Rel family of DNA-binding proteins. In humans, this family is composed of c-Rel, Rel B, p50, p52, and Rel A (p65) which, when bound in the cytoplasm to inhibitor of NF-B (IB) proteins, are inactive. 10,11 Various factors, including ligation of CD40 or the B-cell receptor (BCR), result in proteosomal degradation of IB releasing NF-B, which then translocates to the nucleus. 10,11 Once in the nucleus, NF-B can enhance survival by inducing apoptosis inhibitory proteins, including inhibitor of apoptosis proteins (IAPs), Fas-associated death domain (FADD)-like interleukin (IL)-1␤-converting enzyme (FLICE), and FADD-like IL-1␤-converting enzyme-inhibitory protein (FLIP). 12-14 CLL cells have been reported to exhibit high constitutive NF-B activation compared with normal B lymphocytes. [15][16][17] Although the exact factors responsible for the constitutive expression of NF-B are not fully resolved, many factors, including Akt activation, BCR signaling, CD40 ligation, IL-4, and B-cell activating factor (BAFF), have been shown to increase NF-B activity and enhance CLL cell survival, with members of the Bcl-2 family being principal transcriptional targets. [18][19][20][21][22] Several recent studies have demonstrated the proof of concept of the effectiveness of targeting NF-B in hematologic malignancies, including CLL 23,24 and acute myeloid leukemia. 25,26 In this study, we first set out to determine the range of constitutive DNA binding of NF-B within our patient cohort and to characterize the specific subunits of NF-B in these primary CLL cells. We then went on to investigate the ability of freshly isolated CLL cells to induce NF-B expression in response to BCR Submitted November 20, 2007; accepted January 25, 2008. Prepublished online as Blood First Edition paper, January 28, 2008; DOI 10.1182 DOI 10. /blood-2007 An Inside Blood analysis of this article appears at ...

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Section: Discussionmentioning

confidence: 99%

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

Hewamana

Alghazal²,

Lin³

et al. 2008

Blood

143

132

View full text Add to dashboard Cite

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“…Webb et al (1998) in a study including NHL as well as CLL demonstrated increased expression of MDR1 and MRP in leukaemia-and lymphoma-cells of patients that had been exposed to high doses of P-gp transportable drugs. Quite in contrast, Consoli et al (2002) in a very recent work found no correlation between P-gp, MRP-, and LRP-expression and the amount of previous treatment but, rather, a correlation between Bcl-2 and disease stage. In conclusion, the mechanisms of cellular MDR in CLL have been investigated to some extent.…”

Section: Drug Resistance In Cllmentioning

confidence: 82%

Genes of multidrug resistance in haematological malignancies

et al. 2006

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Since the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistanceassociated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.

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“…To our knowledge, the expression of LRP in CLL has been reported in only one study. Consoli et al 47 stated that no differences were observed in CLL patients when patients were grouped as untreated and treated with at least one line of treatment. However, significantly higher levels of LRP protein were measured in MRP-positive than in MRP-negative patients.…”

Section: Discussionmentioning

confidence: 99%

Expression of Multidrug Resistance 1, Lung Resistance Protein and Breast Cancer Resistance Protein Genes in Chronic Leukemias

İşeri¹

2011

UHOD

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One of the major problems in treatment of leukemias is multidrug resistance, which is already present at diagnosis or develops after chemotherapy. The gene expression levels of multidrug resistance resistance 1 (MDR1), breast cancer resistance protein (BCRP) and lung resistance-resistance protein (LRP) were evaluated in blood samples of 20 CLL and 24 CML patients using RT-PCR. MDR1, BCRP and LRP expression levels were detected in 65%, 20% and 45% of CLL patients, and in 54%, 37% and 25% of CML patients, respectively. 20% of CLL patients and 33% of CML patients expressed none of the genes. The other 20% of CLL patients expressed all the genes. 17% of CML patients expressed all of these genes, and two of them rapidly progressed to acute leukemia. MDR and LRP expressions seem to be frequent events in CLL and CML patients; however no conclusion can be drawn on their prognostic role and response to the treatment. Lösemi tedavisinde en önemli problemlerden birisi hastada zaten var olan veya kemoterapi s›ras›nda geliflen, kemoterapötik ilaçlara karfl› ilaç direncinin geliflmesidir. Çoklu ilaç dirençlili¤i genleri olan MDR1, BCRP, LRP gen ifadeleri 20 KLL ve 24 KML hastas›nda GT-PZR metoduyla belirlenmifltir. Çoklu ilaç dirençlili¤i genleri olan MDR1, BCRP, LRP gen ifadeleri 20 KLL ve 24 KML hastas›nda GT-PZR metoduyla belirlenmifltir. MDR1, BCRP ve LRP gen ifade düzeyleri KLL vakalar›n›n s›ras›yla %65, %20 ve %45'inde; KML vakalar›n›n ise %54, %37 ve %25'inde bulunmufltur. KLL vakalar›n›n %20'sinde ve KML vakalar›n›n %33'ünde ise genlerin ifadeleri gözlenmemifltir. KLL hastalar›n›n di¤er %20'si ise incelenen genleri ifade etmifllerdir. KML hastalar›n›n %17'si her üç geni ifade etmifller ve hastalardan ikisi akut lösemiye h›zl› bir flekilde geçifl göstermifllerdir. MDR1 ve LRP gen ifadelerinin KLL ve KML için anlaml› oldu¤u anlafl›lmaktad›r. Ancak, gen ifadelerinin prognostik önemlerinin belirlenebilmesi aç›s›ndan anlaml› bir sonuç ç›kar›lamam›flt›r. ficant association was found between the treatment and the expression of the other resistance related genes (BCRP, LRP). According to Mann-Whitney test for continuous variables, the median of disease age for patients with observed MDR1 expression was significantly lower than the median of disease age for patients with no MDR1 expression (p= 0.014). However the distribution of age was not significantly different in patients with or without MDR1 expression. The distribution of neither age nor disease age was significantly different for patients with or without BCRP and LRP gene expressions. According to Fisher's exact test for gene expression associations, there was no significant association among three genes analyzed. Resistance related gene expression of CML patientsThe ages of the patients were between 24 and 71 with a median of 41 years, and the time from diagnosis up to RNA isolation varied between less than 1 to 12 years with a median of 2 years (Table 1). Eighteen of 24 patients had chemotherapy at the time of blood sampling. Details of chemotherapy given to p...

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Multidrug resistance mechanisms in chronic lymphocytic leukaemia

Cited by 37 publications

References 30 publications

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

Genes of multidrug resistance in haematological malignancies

Expression of Multidrug Resistance 1, Lung Resistance Protein and Breast Cancer Resistance Protein Genes in Chronic Leukemias

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