Nathalie Meuleman

Institut Jules Bordet, Bruxelles, Brussels Capital, Belgium

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Publications (61)221.05 Total impact

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    ABSTRACT: Little is known about the reliability of G8 screening tool and the prognostic value of clinical parameters within the Comprehensive Geriatric Assessment (CGA) in clinically fit older patients with hematological malignancies. This study was performed to assess the reliability of G8 as a screening tool and to determine the predictive value of CGA items in terms of 1-year overall survival (OS). G8 and CGA were proposed to 107 consecutive patients (65-89years) with hematological malignancies assessed by their physicians as clinically fit, meaning not exhibiting geriatric syndromes and/or irreversible comorbidities significantly impairing their daily function, and thus able to receive chemotherapy. Out of 107 patients, 90 patients were evaluable and completed both scales; 72% and 80% were defined as "vulnerable" when evaluated with G8 (≤14.5) or CGA (≥2 impairments) respectively. The area under ROC-curve of G8 compared to CGA was 0.749±0.051. Neither G8 nor CGA total scores were predictive of 1-year OS. However, age (HR=1.105, 95% CI: 1.016-1.202; p=0.019), diagnosis (HR=5.208, 95% CI: 1.895-14.310; p=0.001) and cognitive status (HR=3.260, 95% CI: 1.043-10.194; p=0.042) were predictive of OS. We conclude that in our selected hematological patients: 1) the G8 score does not help selecting patients for CGA, 2) the G8 and CGA total scores do not predict OS, and 3) in addition to the age and disease itself, cognitive impairment appears to be a powerful prognostic factor. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Geriatric Oncology 08/2015; DOI:10.1016/j.jgo.2015.07.006 · 1.86 Impact Factor
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    ABSTRACT: Preparations of Mesenchymal Stromal Cells (MSC) are generally obtained from unfractionated tissue cells resulting in heterogeneous cell mixtures. Several markers were proposed to enrich these cells but the majority of these markers are defined for Bone Marrow (BM). Moreover, the surface markers of freshly isolated MSC also differ from those of cultured MSC in addition of a phenotypic variation depending on the MSC source. For tissue engineering applications, it is crucial to start with a well-defined cell population. In this study, we performed immunomagnetic selections with 5 single surface markers to isolate MSC subpopulations from BM and Adipose Tissue (AT): CD271, SUSD2, MSCA-1, CD44 and CD34. We determined the phenotype, the clonogenicity, the proliferation, the differentiation capacity and the immunoregulatory profile of the sub-populations obtained in comparison with unselected cells. We showed that native BM-MSC can be enriched from the positive fractions of MSCA-1, SUSD2 and CD271 selections. In contrast, we observed that SUSD2 and MSCA-1 were unable to identify MSC from AT meaning they are not expressed in situ. Only the CD34+ selection successfully isolated MSC from AT. Interestingly, we observed that CD271 selection can define AT cell subsets with particular abilities but only in lipoaspiration samples, not in abdominoplasties samples. Importantly, we found a population of clearly CD34+ fresh BM-MSC displaying different properties. A single marker-based selection for MSC enrichment should be more advantageous for cell therapy and would enable the standardization of efficient and safe therapeutic intervention through the use of a well identified and homogeneous cell population.
    Stem cells and development 06/2015; 24(18). DOI:10.1089/scd.2015.0172 · 3.73 Impact Factor
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    ABSTRACT: Purpose: To compare using immuno-PET/CT the distribution of (89)Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with (90)Y-labelled rituximab in CD20+ B-cell lymphoma. Methods: Five patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline (89)Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m(2)) of unlabelled rituximab followed by injection of (89)Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by (90)Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed. Results: With a cold rituximab preload, the calculated whole-body dose of (90)Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82-0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59% and 87% was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion. Conclusion: Administration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the "prerituximab era". Clinical Trial Application: CTA 2011-005474-38 TRIAL REGISTRY: EudraCT.
    European journal of nuclear medicine and molecular imaging 03/2015; 42(8). DOI:10.1007/s00259-015-3025-6 · 5.38 Impact Factor
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    ABSTRACT: MicroRNAs (or miRs) play a crucial role in chronic lymphocytic leukemia (CLL) physiopathology and prognosis. In addition, circulating microRNAs in body fluids have been proposed as new biomarkers. We investigated the expression of matched cellular and serum circulating microRNA-150 by real-time PCR (qPCR) from purified CD19+ cells or from CLL serums obtained at diagnosis in a cohort of 273/252 CLL patients with a median follow-up of 78 months (range, 7-380) and correlated it to other biological or clinical parameters. We showed that miR-150 was significantly overexpressed in CLL cells/serums compared to healthy subjects (P<0.0001). Among CLL patients, a low cellular miR-150 expression level was associated with tumor burden, disease aggressiveness and poor prognostic factors. In contrast, a high level of serum miR-150 was associated with tumor burden markers and some markers of poor prognosis. Similarly, cellular and serum miR-150 also predicted treatment-free (TFS) and overall survival (OS) in an opposite manner: patients with low cellular/serum miR-150 levels have median TFS of 40/111 months compared with high level patients who have median TFS of 122/60 months (P<0.0001/P=0.0066). Similar results have been observed for OS. We also found that cellular and serum miR-150 levels vary in an opposite manner during disease progression and that cellular miR-150 could be regulated by its release into the extracellular space. Cellular and serum levels of miR-150 are associated with opposite clinical prognoses and could be used to molecularly monitor disease evolution as a new prognostic factor in CLL.
    Molecular Medicine 01/2015; 21. DOI:10.2119/molmed.2014.00214 · 4.51 Impact Factor
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    ABSTRACT: In multiple myeloma (MM), bone marrow mesenchymal stromal cells (BM-MSCs) play an important role in pathogenesis and disease progression by supporting myeloma cell growth and immune escape. Previous studies have suggested that direct and indirect interactions between malignant cells and BM-MSCs result in constitutive abnormal immunomodulatory capacities in MM BM-MSCs. The aim of this study was to investigate the mechanisms that underlie these MM BM-MSCs abnormalities. We demonstrated that MM BM-MSCs exhibit abnormal expression of CD40/40L, VCAM1, ICAM-1, LFA-3, HO-1, HLA-DR and HLA-ABC. Furthermore, an overproduction of IL-6 (1,806 ± 152.5 vs 719.6 ± 18.22 ng/mL; p = 0.035) and a reduced secretion of IL-10 (136 ± 15.02 vs 346.4 ± 35.32 ng/mL; p = 0.015) were quantified in culture medium when MM BM-MSCs were co-cultured with T lymphocytes compared to co-cultures with healthy donor (HD) BM-MSCs. An increased Th17/Treg ratio was observed when T cells were co-cultured with MM BM-MSCs compared to co-cultures with HD BM-MSCs (0.955 vs 0.055). Together, these observations demonstrated that altered immunomodulation capacities of MM BM-MSCs were linked to variations in their immunogenicity and secretion profile. These alterations lead not only to a reduced inhibition of T cell proliferation but also to a shift in the Th17/Treg balance. We identified factors that are potentially responsible for these alterations, such as IL-6, VCAM-1 and CD40, which could also be associated with MM pathogenesis and progression.
    Cancer Immunology and Immunotherapy 10/2014; 64(2). DOI:10.1007/s00262-014-1623-y · 3.94 Impact Factor
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    ABSTRACT: Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and >376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment.
    Epigenetics: official journal of the DNA Methylation Society 10/2014; 9(10):1374-81. DOI:10.4161/15592294.2014.969628 · 4.78 Impact Factor
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    ABSTRACT: Stem cell therapy is a potential method for the treatment of numerous diseases. The most frequent cellular source is bone marrow-derived mesenchymal stromal cells (BM-MSC). Human adipose-derived stromal cells (ADSC) share similar properties with BM-MSC as they support hematopoiesis, modulate ongoing immune responses and differentiate into cells of mesodermal origin. On the other hand, ADSC have higher frequency in situ, higher availability and very few ethical issues compared to BM-MSC giving them an advantage over BM-MSC for clinical use. Most of the methods used to isolate ADSC contain a collagenase digestion step, but the type of collagenase and time of sample digestion vary among studies and these differences could have an impact on the cell properties and thus in result comparison. To overcome this obstacle, we propose a new method to isolate ADSC from lipoaspirate without collagenase digestion step. We compared ADSC obtained with our method versus classical protocol using collagenase digestion. Cells obtained with our method are equivalent but has a better long term hematopoietic support than those obtained with classical method. Moreover, our method has an advantage over the classical one as it is easier, safer, faster, less expensive and more consistent with good manufacturing practices (GMP) to obtain large number of ADSC ex vivo.
    Stem cells and development 05/2014; 23(19). DOI:10.1089/scd.2014.0071 · 3.73 Impact Factor
  • Journal of Geriatric Oncology 10/2013; 4:S56. DOI:10.1016/j.jgo.2013.09.077 · 1.86 Impact Factor
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    ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.
    Revue medicale de Bruxelles 09/2013; 34(4):335-8.
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    ABSTRACT: Autologous mesenchymal stromal cell (MSC)-based therapies offer one of the most promising and safe methods for regeneration or reconstruction of tissues and organs. Routinely procedures to obtain adequate amount of autologous stem cells need their expansion through culture, with risks of contamination and cell differentiation, leading to loss of cell ability for therapies. We suggest the use of human bone marrow as a physiological bioreactor to produce autologous MSC by injection of autologous platelet-rich plasma (PRP) activated by recombinant human soluble tissue factor (rhsTF) in iliac crest. A trial on thirteen healthy volunteers showed the feasibility and harmlessness of the procedure. The phenotype and cellularity of bone marrow cells were not modified, on day 3 after injection. Endothelial progenitor cells (EPC) were mobilized to bloodstream, without stimulation of hematopoietic stem cells (HSC). MSC level in bone marrow increased with a specific commitment to preosteoblastic cell population both in vivo and in vitro. This self-stimulation system of bone marrow seems thus to be a promising feasible process three days prior to clinical cell therapy applications.
    Tissue Engineering Part A 08/2013; 20(1-2). DOI:10.1089/ten.TEA.2013.0244 · 4.64 Impact Factor
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    ABSTRACT: The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.
    Annals of Medicine 06/2013; 45(5-6). DOI:10.3109/07853890.2013.801562 · 3.89 Impact Factor
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    ABSTRACT: In multiple myeloma, bone marrow mesenchymal stromal cells support myeloma cell growth. Previous studies have suggested that direct and indirect interactions between malignant cells and bone marrow mesenchymal stromal cells result in constitutive abnormalities in the bone marrow mesenchymal stromal cells. The aims of this study were to investigate the constitutive abnormalities in myeloma bone marrow mesenchymal stromal cells and to evaluate the impact of new treatments. We demonstrated that myeloma bone marrow mesenchymal stromal cells have an increased expression of senescence-associated β-galactosidase, increased cell size, reduced proliferation capacity and characteristic expression of senescence-associated secretory profile members. We also observed a reduction in osteoblastogenic capacity and immunomodulatory activity and an increase in hematopoietic support capacity. Finally, we determined that current treatments were able to partially reduce some abnormalities in secreted factors, proliferation and osteoblastogenesis. We showed that myeloma bone marrow mesenchymal stromal cells have an early senescent profile with profound alterations in their characteristics. This senescent state most likely participates in disease progression and relapse by altering the tumor microenvironment.
    PLoS ONE 03/2013; 8(3):e59756. DOI:10.1371/journal.pone.0059756 · 3.23 Impact Factor
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    Journal of Cancer Science and Therapy 11/2012; 4(12):394-400.
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    ABSTRACT: Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an under expression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively. For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo. However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course.
    Epigenetics: official journal of the DNA Methylation Society 10/2012; 7(12). DOI:10.4161/epi.22674 · 4.78 Impact Factor
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    ABSTRACT: Intraarterial administration of 90Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed.
    CardioVascular and Interventional Radiology 09/2012; 36(4). DOI:10.1007/s00270-012-0484-z · 2.07 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) possess a specific immunological profile that makes them potentially useful for immune-based therapies. Adipose tissue (AT) and Wharton's jelly (WJ) are considered to be valuable alternatives to bone marrow (BM) as sources of MSCs. These MSCs exhibit strong immunomodulatory properties that affect lymphocyte responses. The CD200/CD200R axis has been reported to be important in regulating the immune responses. Engagement of CD200R by CD200 initiates an inhibitory pathway that displays immunosuppressive effects. Because the CD200/CD200R axis is involved in immunoregulation, we investigated the expression and role of this ligand/receptor pair in MSCs and T-lymphocytes during co-culture. CD200 is differently expressed and modulated on MSCs depending on the tissue of origin and the culture conditions. Among the different MSC sources, WJ-MSCs express CD200 in the greatest proportion. This high constitutive CD200 expression may represent a distinctive marker for WJ-MSCs. A pro-inflammatory environment and IFN-γ in particular induce an increase in CD200 expression by BM-MSCs. In T-lymphocytes, CD200R and CD200 are differently distributed between the CD4(+) and CD8(+) T-cell subsets. During co-culture, blocking CD200-CD200R interactions does not prevent MSC-mediated inhibition of lymphocyte proliferation. However, depending on their origin, MSCs are able to modulate the expression of both CD200 and CD200R on some T-cells. Further study is required to understand the function of CD200 expression by nonmyeloid cells such MSCs and the significance of CD200 and C200R expression by T-cells. The findings presented here support bidirectional communication between MSCs and T-lymphocytes. Understanding the role of this ligand-receptor pair during co-culture will improve and increase the clinical use of MSCs.
    Immunology letters 05/2012; 146(1-2):50-6. DOI:10.1016/j.imlet.2012.04.017 · 2.51 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) can be isolated not only from bone marrow (BM) but also from other tissues, including adipose tissue (AT) and umbilical cord Wharton's Jelly (WJ). Thanks to their ability to differentiate into various cell types, MSC are considered attractive candidates for cell-based regenerative therapy. In degenerative clinical settings, inflammation or infection is often involved. In the present work, we hypothesized that an inflammatory environment and/or Toll-like receptor (TLR) ligation could affect the MSC differentiation potential. MSC were isolated from BM, AT, and WJ. Inflammation was mimicked by a cytokine cocktail, and TLR activation was induced through TLR3 and TLR4 ligation. Osteogenesis was chosen as a model for differentiation. Osteogenic parameters were evaluated by measuring Ca2+ deposits and alkaline phosphatase (ALP) activity at day 7, 14, and 21 of the culture in an osteogenic medium. Our results show that WJ-MSC exhibit a much lower osteogenic potential than the other two MSC types. However, inflammation was able to strongly increase the osteogenic differentiation of WJ-MSC as calcification, and ALP activity appeared as early as day 7. However, this latter enzymatic activity remained much lower than that disclosed by BM-MSC. TLR3 or TLR4 triggering increased the osteogenesis in AT- and, to lesser extent, in BM-MSC. In conclusion, WJ-MSC constitutively disclose a lower osteogenic potential as compared with BM and AT-MSC, which is not affected by TLR triggering but is strongly increased by inflammation, then reaching the level of BM-MSC. These observations suggest that WJ-MSC could constitute an alternative of BM-MSC for bone regenerative applications, as WJ is an easy access source of large amounts of MSC that can effectively differentiate into osteoblasts in an inflammatory setting.
    Tissue Engineering Part A 03/2012; 18(13-14):1410-8. DOI:10.1089/ten.TEA.2011.0434 · 4.64 Impact Factor
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    ABSTRACT: Interactions with the microenvironment, such as bone marrow mesenchymal stromal cells and nurse-like cells, protect chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis. This protection is partially mediated by the chemokine SDF-1α (CXCL12) and its receptor CXCR4 (CD184) present on the chronic lymphocytic leukemia cell surface. Here, we investigated the ability of AMD3100, a CXCR4 antagonist, to sensitize chronic lymphocytic leukemia cells to chemotherapy in a chronic lymphocytic leukemia/mesenchymal stromal cell based or nurse-like cell based microenvironment co-culture model. AMD3100 decreased CXCR4 expression signal (n=15, P=0.0078) and inhibited actin polymerization/migration in response to SDF-1α (n=8, P<0.01) and pseudoemperipolesis (n=10, P=0.0010), suggesting that AMD3100 interferes with chronic lymphocytic leukemia cell trafficking. AMD3100 did not have a direct effect on apoptosis when chronic lymphocytic leukemia cells were cultured alone (n=10, P=0.8812). However, when they were cultured with SDF-1α, mesenchymal stromal cells or nurse-like cells (protecting them from apoptosis, P<0.001), chronic lymphocytic leukemia cell pre-treatment with AMD3100 significantly inhibited these protective effects (n=8, P<0.01) and decreased the expression of the anti-apoptotic proteins MCL-1 and FLIP. Furthermore, combining AMD3100 with various drugs (fludarabine, cladribine, valproïc acid, bortezomib, flavopiridol, methylprednisolone) in our mesenchymal stromal cell co-culture model enhanced drug-induced apoptosis (n=8, P<0.05) indicating that AMD3100 could mobilize chronic lymphocytic leukemia cells away from their protective microenvironment, making them more accessible to conventional therapies. Taken together, these data demonstrate that interfering with the SDF-1α/CXCR4 axis by using AMD3100 inhibited chronic lymphocytic leukemia cell trafficking and microenvironment-mediated protective effects. Combining AMD3100 with other drugs may, therefore, represent a promising therapeutic approach to kill chronic lymphocytic leukemia cells.
    Haematologica 11/2011; 97(4):608-15. DOI:10.3324/haematol.2011.052779 · 5.81 Impact Factor
  • Clinical Lymphoma, Myeloma and Leukemia 10/2011; 11:S255-S256. DOI:10.1016/j.clml.2011.09.173 · 2.02 Impact Factor

Publication Stats

1k Citations
221.05 Total Impact Points


  • 2000–2015
    • Institut Jules Bordet
      • Department of Nuclear Medicine
      Bruxelles, Brussels Capital, Belgium
  • 2013
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 2003–2012
    • Université Libre de Bruxelles
      • • Laboratory of Clinical Cell Therapy
      • • Laboratory of Experimental Hematology
      • • Bordet Institute
      • • Department of Hematology
      Bruxelles, Brussels Capital, Belgium
    • Hôpital Universitaire des Enfants Reine Fabiola
      • Department of Hemato-Oncology
      Bruxelles, Brussels Capital Region, Belgium
  • 2002
    • University Hospital Brussels
      Bruxelles, Brussels Capital, Belgium