References of "Willems, Luc"
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See detailPreclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy
Hubaux, Roland; Vandermeers, Fabian ULg; Crisanti, Cecilia et al

in European Journal of Cancer (2010), 46

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years.We hypothesized that SCLC chemotherapy could be improved by ... [more ▼]

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years.We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin + etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18 kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na+/ K+ ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer. [less ▲]

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See detailFacilitating studies of cell proliferation in chronic lymphocytic leukemia
Macallan, Derek C.; Defoiche, Julien; Willems, Luc ULg

in Leukemia Research (2010), 34

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See detailNovel HDAC/DNMT twin inhibitors interfere with angiogenesis
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice; Blacher, Silvia ULg et al

Poster (2010)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent antiangiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, very little work has been done to understand the effect of this combination on normal and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (endothelial cells, pericytes and the 3D aortic ring assay) and in vivo (the chick chorioallantoic membrane assay). We have identified a lead compound having quantifiable antiangiogenic effect without cytotoxicity associated with increased global acetylation and decreased DNA methylation levels. This compound is presently used to develop effective approaches to treat cancer by modulating the process of angiogenesis. [less ▲]

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See detailLong-term treatment with valproic acid does not alleviate the condition of HAM/TSP
Olindo, S.; Belrose, G.; Lezin, A. et al

in AIDS Research and Human Retroviruses (2009, July 01), 25(11), 21

Long-Term Treatment with Valproic Acid Does Not Alleviate the Condition of HAM/TSP Olindo, S.,1 Belrose, G.,2 Lezin, A.,2 Gillet, N.,3 Defoiche, J.,4 Rodriguez, S.,4 Signaté, A.,1 Verlaeten, O.,4 Smadja ... [more ▼]

Long-Term Treatment with Valproic Acid Does Not Alleviate the Condition of HAM/TSP Olindo, S.,1 Belrose, G.,2 Lezin, A.,2 Gillet, N.,3 Defoiche, J.,4 Rodriguez, S.,4 Signaté, A.,1 Verlaeten, O.,4 Smadja, D.,1 Césaire, R.,2 Willems, L.4 1Service de Neurologie and JE 2503, Centre Hospitalier Universitaire de Fort-de-France, 97200 Fort-de-France, Martinique, France; 2Laboratoire de Virologie-Immunologie and JE 2503, Centre Hospitalier Universitaire de Fort-de-France, 97200 Fort-de-France, Martinique, France; 3Department of Immunology, Imperial College, London, UK; 4Molecular and Cellular Biology, University Academia ‘‘Wallonie-Europe’’, 5030 Gembloux, Belgium. LW is Research Director of the FNRS. We previously proposed to interfere with proviral loads in HAM/TSP patients by modulating lysine deacetylase activity using valproic acid (VPA). The strategy aims at activating viral gene expression in order to expose virus-positive cells to the host immune response. We conducted a single-center, two-year open-label trial, with 19 HAM/TSP volunteers treated with oral doses of VPA (20mg/Kg/day). Objectives were to assess biological response and clinical safety to VPA treatment in HAM/TSP patients. By microarray analysis, we show that VPA treatment moderately stimulated expression of cyclinD2 and Rho GTPase activating protein 18 in CD4-T cells. CD8-mediated lysis efficiency of Tax-expressing cells was unaltered by VPA treatment. The CD4-T cell turnover rate was calculated by GC/MS analysis from quantitative incorporation of deuterium into DNA. Transient increase in proviral loads correlated with accelerated proliferation. After 2 years, the proviral loads reached levels similar to those before treatment. The main clinical side effects were drowsiness (52%), tremor (47%), digestive symptoms (37%), vertigo (26%), and alopecia (10%). The frequency of side symptoms tended to decrease over the trial course. The neurological status over the study constituted the primary clinical safety measures. Disability Status Scale, muscle testing score, Ashworth score, and urinary dysfunction score showed no significant changes. Walking Time Test (WTT) slightly varied over the study except in 3 patients in whom the WTT variation rates were>20%. These 3 patients experienced drowsiness and tremor and improved rapidly after treatment discontinuation. Together, these observations indicated that long term treatment with VPA is safe but does not alleviate the condition of HAM/TSP. [less ▲]

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See detailGene activation therapy: from the BLV model to HAM/TSP patients.
Lezin, Agnes; Olindo, Stephane; Belrose, Gildas et al

in Frontiers in Bioscience (Scholar Edition) (2009), 1

HTLV-1 (human T-lymphotropic virus type 1) and BLV (bovine leukemia virus) are two related retroviruses infecting CD4+ and B lymphocytes in humans and ruminants, respectively. During infection, the host ... [more ▼]

HTLV-1 (human T-lymphotropic virus type 1) and BLV (bovine leukemia virus) are two related retroviruses infecting CD4+ and B lymphocytes in humans and ruminants, respectively. During infection, the host-pathogen interplay is characterized by very dynamic kinetics resulting in equilibrium between the virus, which attempts to proliferate, and the immune response, which seeks to exert tight control of the virus. A major determinant of disease induction by both viruses is the accumulation of provirus in peripheral blood. In the absence of viral proteins, virus infected cells escape recognition and destruction by the host immune response. We propose a novel therapeutic strategy based on transient activation of viral expression using epigenetic modulators; this exposes infected cells to the immune response and results in significant reductions in proviral loads. In the absence of satisfactory therapies, this viral gene-activation strategy might delay progression, or even be curative, for HTLV-1 induced myelopathy / tropical spastic paraparesis (HAM/TSP). [less ▲]

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See detailEarlier onset of delta-retrovirus-induced leukemia after splenectomy.
Florins, ARNAUD-FRANCOIS ULg; Reichert, Michal; Asquith, Becca et al

in PLoS ONE (2009), 4(9), 6943

Infection by delta-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of delta-retrovirus infected hosts ... [more ▼]

Infection by delta-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of delta-retrovirus infected hosts will develop either lymphoproliferative or neurodegenerative diseases after long latency periods. In fact, the host immune response is believed to tightly control viral replication but this assumption has not been definitely proven in vivo. Here, we provide direct experimental evidence demonstrating that integrity of the spleen is required to control pathogenesis. In the BLV model, we show that asplenia decreases efficiency of the immune response and induces an imbalance in cell dynamics resulting in accelerated onset of leukemia. These observations enlighten a potential threat in splenectomized HTLV-1 carriers and justify a regular preventive evaluation. [less ▲]

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See detailReduced levels of reactive oxygen species correlate with inhibition of apoptosis, rise in thioredoxin expression and increased bovine leukemia virus proviral loads.
Bouzar, Amel ULg; Boxus, Mathieu ULg; Florins, ARNAUD-FRANCOIS ULg et al

in Retrovirology (2009), 6

BACKGROUND: Bovine Leukemia virus (BLV) is a deltaretrovirus that induces lymphoproliferation and leukemia in ruminants. In ex vivo cultures of B lymphocytes isolated from BLV-infected sheep show that ... [more ▼]

BACKGROUND: Bovine Leukemia virus (BLV) is a deltaretrovirus that induces lymphoproliferation and leukemia in ruminants. In ex vivo cultures of B lymphocytes isolated from BLV-infected sheep show that spontaneous apoptosis is reduced. Here, we investigated the involvement of reactive oxygen species (ROS) in this process. RESULTS: We demonstrate that (i) the levels of ROS and a major product of oxidative stress (8-OHdG) are reduced, while the thioredoxin antioxidant protein is highly expressed in BLV-infected B lymphocytes, (ii) induction of ROS by valproate (VPA) is pro-apoptotic, (iii) inversely, the scavenging of ROS with N-acetylcysteine inhibits apoptosis, and finally (iv) the levels of ROS inversely correlate with the proviral loads. CONCLUSION: Together, these observations underline the importance of ROS in the mechanisms of inhibition of apoptosis linked to BLV infection. [less ▲]

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See detailA Dose-Effect Relationship For Deltaretrovirus-Dependent Leukemogenesis In Sheep
Pomier, Carole; Alcaraz, Maria Teresa Sanchez; Debacq, Christo^phe et al

in Retrovirology (2009), 6

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See detailValproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells.
Bouzar, Amel ULg; Boxus, Mathieu ULg; Defoiche, Julien et al

in British journal of haematology (2009), 144(1),

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See detailValproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.
Vandermeers, Fabian ULg; Hubert, Pascale ULg; Delvenne, Philippe ULg et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2009), 15(8), 2818-28

PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to ... [more ▼]

PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and RESULTS: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. CONCLUSIONS: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma. [less ▲]

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See detailMechanisms of HTLV-1 persistence and transformation.
Boxus, Mathieu ULg; Willems, Luc ULg

in British Journal of Cancer (2009), 101(9), 1497-501

Adult T-cell leukaemia (ATL) is caused by the human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 has elaborated strategies to persist and replicate in the presence of a strong immune response. In ... [more ▼]

Adult T-cell leukaemia (ATL) is caused by the human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 has elaborated strategies to persist and replicate in the presence of a strong immune response. In this review, we summarise these mechanisms and their contribution to T-cell transformation and ATL development. [less ▲]

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See detailThe 14th International Conference on Human Retrovirology: HTLV and related retroviruses (July 1-4, 2009; Salvador, Brazil).
Willems, Luc ULg

in Retrovirology (2009), 6

The "14th International Conference on Human Retrovirology: HTLV and Related Retroviruses" was held in Salvador, Bahia, from July 1st to July 4th 2009. The aim of this biennial meeting is to promote ... [more ▼]

The "14th International Conference on Human Retrovirology: HTLV and Related Retroviruses" was held in Salvador, Bahia, from July 1st to July 4th 2009. The aim of this biennial meeting is to promote discussion and share new findings between researchers and clinicians for the benefit of patients infected by human T-lymphotropic virus (HTLV). HTLV infects approximately 15-20 million individuals worldwide and causes a broad spectrum of diseases including neurodegeneration and leukemia. The scientific program included a breadth of HTLV research topics: epidemiology, host immune response, basic mechanisms of protein function, virology, pathogenesis, clinical aspects and treatment. Exciting new findings were presented in these different fields, and the new advances have led to novel clinical trials. Here, highlights from this conference are summarized. [less ▲]

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See detailMeasurement of ribosomal RNA turnover in vivo by use of deuterium-labeled glucose.
Defoiche, Julien; Zhang, Yan; Lagneaux, Laurence et al

in Clinical Chemistry (2009), 55(10), 1824-33

BACKGROUND: Most methods for estimation of rates of RNA production are not applicable in human in vivo clinical studies. We describe here an approach for measuring ribosomal RNA turnover in vivo using [6 ... [more ▼]

BACKGROUND: Most methods for estimation of rates of RNA production are not applicable in human in vivo clinical studies. We describe here an approach for measuring ribosomal RNA turnover in vivo using [6,6-(2)H(2)]-glucose as a precursor for de novo RNA synthesis. Because this method involves neither radioactivity nor toxic metabolites, it is suitable for human studies. METHODS: For method development in vitro, a lymphocyte cell line (PM1) was cultured in the presence of [6,6-(2)H(2)]-glucose. RNA was extracted, hydrolyzed enzymatically to ribonucleosides, and derivatized to either the aldonitrile tetra-acetate or the pentafluoro triacetate derivative of the pentose before GC-MS. We identified optimum derivatization and analysis conditions and demonstrated quantitative incorporation of deuterium from glucose into RNA of dividing cells. RESULTS: Pilot clinical studies demonstrated the applicability of this approach to blood leukocytes and solid tissues. A patient with chronic lymphocytic leukemia received [6,6-(2)H(2)]-glucose (1 g/kg) orally in aliquots administered every 30 min for a period of 10 h. When we analyzed CD3(-) B cells that had been purified by gradient centrifugation and magnetic-bead adhesion, we observed deuterium enrichment, a finding consistent with a ribosomal RNA production rate of about 7%/day, despite the slow division rates observed in concurrent DNA-labeling analysis. Similarly, in 2 patients with malignant infiltration of lymph nodes, administration of [6,6-(2)H(2)]-glucose (by intravenous infusion for 24 h) before excision biopsy allowed estimation of DNA and RNA turnover in lymph node samples. CONCLUSIONS: Our study results demonstrate the proof-of-principle that deuterium-labeled glucose may be used to analyze RNA turnover, in addition to DNA production/cell proliferation, in clinical samples. [less ▲]

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See detailEmphasis on cell turnover in two hosts infected by bovine leukemia virus: a rationale for host susceptibility to disease.
Florins, Arnaud-Francois ULg; Boxus, Mathieu ULg; Vandermeers, Fabian ULg et al

in Veterinary Immunology and Immunopathology (2008), 125(1-2), 1-7

Bovine leukemia virus (BLV) is a deltaretrovirus that infects and induces accumulation of B-lymphocytes in the peripheral blood and lymphoid tissues of cattle, leading to leukemia/lymphoma. BLV can also ... [more ▼]

Bovine leukemia virus (BLV) is a deltaretrovirus that infects and induces accumulation of B-lymphocytes in the peripheral blood and lymphoid tissues of cattle, leading to leukemia/lymphoma. BLV can also be experimentally transmitted to sheep, in which disease appears earlier and at higher frequencies. Abnormal accumulation of leukemic B-lymphocytes results from an alteration of different parameters that include cell proliferation and death as well as migration to lymphoid tissues. Interestingly, B lymphocyte turnover is increased in BLV-infected sheep but reduced in cattle, revealing a potential relationship between cell kinetics and disease progression. [less ▲]

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See detailEarly and transient reverse transcription during primary deltaretroviral infection of sheep.
Pomier, Carole; Alcaraz, Maria Teresa Sanchez; Debacq, Christophe et al

in Retrovirology (2008), 5

BACKGROUND: Intraindividual genetic variability plays a central role in deltaretrovirus replication and associated leukemogenesis in animals as in humans. To date, the replication of these viruses has ... [more ▼]

BACKGROUND: Intraindividual genetic variability plays a central role in deltaretrovirus replication and associated leukemogenesis in animals as in humans. To date, the replication of these viruses has only been investigated during the chronic phase of the infection when they mainly spread through the clonal expansion of their host cells, vary through a somatic mutation process without evidence for reverse transcriptase (RT)-associated substitution. Primary infection of a new organism necessary involves allogenic cell infection and thus reverse transcription. RESULTS: Here we demonstrate that the primary experimental bovine leukemia virus (BLV) infection of sheep displays an early and intense burst of horizontal replicative dissemination of the virus generating frequent RT-associated substitutions that account for 69% of the in vivo BLV genetic variability during the first 8 months of the infection. During this period, evidence has been found of a cell-to-cell passage of a mutated sequence and of a sequence having undergone both RT-associated and somatic mutations. The detection of RT-dependent proviral substitution was restricted to a narrow window encompassing the first 250 days following seroconversion. CONCLUSION: In contrast to lentiviruses, deltaretroviruses display two time-dependent mechanisms of genetic variation that parallel their two-step nature of replication in vivo. We propose that the early and transient RT-based horizontal replication helps the virus escape the first wave of host immune response whereas somatic-dependent genetic variability during persistent clonal expansion helps infected clones escape the persistent and intense immune pressure that characterizes the chronic phase of deltaretrovirus infection. [less ▲]

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See detailImplication des modifications épigénétiques dans les cancers : développement de nouvelles approches thérapeutiques
Vandermeers, Fabian ULg; Kettmann, Richard ULg; Willems, Luc ULg

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (2008), 12(2),

Involvement of epigenetic modifications in cancers: development of new therapeutic approaches. Since cancer is the second cause of death after cardiovascular diseases in industrialized countries, it is ... [more ▼]

Involvement of epigenetic modifications in cancers: development of new therapeutic approaches. Since cancer is the second cause of death after cardiovascular diseases in industrialized countries, it is urgent to elaborate new therapeutic approaches. Besides DNA mutations of essential genes, expansion of a cancer cell is frequently associated with epigenetic modifications i.e. not directly coded by the DNA sequence. Amongst epigenetic modifications, histones acetylation and DNA methylation are known to play important roles. In this context, a very promising anticancer therapy would be to correct epigenetic errors using compounds modulating histone acetylation and DNA methylation alone or in combination with other chemotherapeutic agents. [less ▲]

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See detailThe HTLV-1 Tax interactome.
Boxus, Mathieu ULg; Twizere, Jean-Claude ULg; Legros, Sebastien et al

in Retrovirology (2008), 5

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to ... [more ▼]

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far. [less ▲]

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See detailHow HTLV-1 may subvert miRNAs for persistence and transformation.
Bouzar, Amel ULg; Willems, Luc ULg

in Retrovirology (2008), 5

Distinct mechanisms are used by viruses to interact with cellular miRNAs. The role of microRNAs in viral replication and persistence ranges from viral-encoded microRNAs to suppressors of RNA interference ... [more ▼]

Distinct mechanisms are used by viruses to interact with cellular miRNAs. The role of microRNAs in viral replication and persistence ranges from viral-encoded microRNAs to suppressors of RNA interference. Viruses can also exploit cellular miRNAs for influencing cellular metabolism to ensure efficient replication or latency. In particular, two recent studies provide examples of how HTLV-1 may co-opt or subvert cellular miRNAs for persistent replication and oncogenic purposes. The pathways modulated by these described miRNAs are critically involved in apoptosis, proliferation and innate immune response. [less ▲]

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See detailReduction of B cell turnover in chronic lymphocytic leukaemia.
Defoiche, Julien; Debacq, Christophe; Asquith, Becca et al

in British Journal of Haematology (2008), 143(2), 240-7

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by ... [more ▼]

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B-cell kinetics in CLL subjects and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-(2)H(2)-glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0.47 vs. 1.31%/d respectively, P = 0.007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B-cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies. [less ▲]

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