Publications by authors named "Stéphanie Lagarde"

14 Publications

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The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Belgian Cancer Registry, Brussels, Belgium.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as TSLC1, Tumour Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid to myeloid ratio in bone marrow although not altering their multi-lineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM and CBL and mutations of ASXL1, SF3B1 and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2021005311DOI Listing
October 2021

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine.

PLoS One 2020 1;15(10):e0238795. Epub 2020 Oct 1.

Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529302PMC
November 2020

Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia.

Clin Cancer Res 2020 07 27;26(13):3307-3318. Epub 2020 Mar 27.

INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France.

Purpose: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.

Experimental Design: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.

Results: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRAS functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.

Conclusions: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334063PMC
July 2020

PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice.

Proc Natl Acad Sci U S A 2018 10 26;115(41):10357-10362. Epub 2018 Sep 26.

Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III Paul Sabatier (UPS), 31037 Toulouse, France;

is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed to the coding sequence of elastin (). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on , , , and genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
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http://dx.doi.org/10.1073/pnas.1721678115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187160PMC
October 2018

and isoforms are both efficient to drive B cell differentiation.

Oncotarget 2018 Aug 28;9(67):32841-32854. Epub 2018 Aug 28.

Inserm, UMR1037 CRCT, F-31000, Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Oncopole, F-31000 Toulouse, France.

Pax5 is the guardian of the B cell identity since it primes or enhances the expression of B cell specific genes and concomitantly represses the expression of B cell inappropriate genes. The tight regulation of is therefore required for an efficient B cell differentiation. A defect in its dosage can translate into immunodeficiency or malignant disorders such as leukemia or lymphoma. is expressed from two different promoters encoding two isoforms that only differ in the sequence of their first alternative exon. Very little is known regarding the role of the two isoforms during B cell differentiation and the regulation of their expression. Our work aims to characterize the mechanisms of regulation of the expression balance of these two isoforms and their implication in the B cell differentiation process using murine analyses. We show that these two isoforms are differentially regulated but have equivalent function during early B cell differentiation and may have functional differences after B cell activation. The tight control of their expression may thus reflect a way to finely tune Pax5 dosage during B cell differentiation process.
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http://dx.doi.org/10.18632/oncotarget.26003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132355PMC
August 2018

Oncostatin M decreases interleukin-1 β secretion by human synovial fibroblasts and attenuates an acute inflammatory reaction in vivo.

J Cell Mol Med 2012 Jun;16(6):1274-85

Centre de Recherche en Rhumatologie et Immunologie du CHUQ, and Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Quebec City, QC, Canada.

Oncostatin M (OSM) is a pleiotropic cytokine of the IL-6 family and displays both pro-inflammatory and anti-inflammatory activities. We studied the impact of OSM on the gene activation profile of human synovial cells, which play a central role in the progression of inflammatory responses in joints. In synovial cells stimulated with lipopolysaccharide and recombinant human granulocyte-macrophage colony-stimulating factor, recombinant human OSM and native OSM secreted by human granulocytes both reduced the gene expression and secretion of IL-1β and CXCL8, but increased that of IL-6 and CCL2. This impact on synovial cell activation was not obtained using IL-6 or leukaemia inhibitory factor. Signal transducer and activator of transcription-1 appeared to mediate the effects of OSM on stimulated human synovial fibroblasts. In the murine dorsal air pouch model of inflammation, OSM reduced the expression of the pro-inflammatory cytokines IL-1β and TNF-α in lining tissues, and their presence in the cavity. These results as a whole suggest an anti-inflammatory role for OSM, guiding inflammatory processes towards resolution.
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http://dx.doi.org/10.1111/j.1582-4934.2011.01412.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823080PMC
June 2012

The pronociceptive effect of proteinase-activated receptor-4 stimulation in rat knee joints is dependent on mast cell activation.

Pain 2011 Feb;152(2):354-360

Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alta., Canada T2N 4N1 Centre de Recherche en Rhumatologie et Immunologie du CHUQ, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Que., Canada.

Proteinase-activated receptor-4 (PAR(4)) is a G-protein-coupled receptor activated by serine proteinases released during tissue repair and inflammation. We have previously shown that PAR(4) activation sensitises articular primary afferents leading to joint pain. This study examined whether mast cells contribute to this PAR(4)-induced sensitisation and consequent heightened pain behaviour. The expression of PAR(4) on synovial mast cells was confirmed with immunofluorescent staining of rat knee joint sections. Electrophysiological recordings were made from joint primary afferents in male Wistar rats during both nonnoxious and noxious rotations of the knee. Afferent firing rate was recorded for 15 minutes after close intra-arterial injection of 10(-9) to 10(-5)mol of the PAR(4) activating peptide, AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100-μl bolus). Rats were either naive or pretreated with the mast cell stabilise, cromolyn (20mg/kg). Mechanical withdrawal thresholds were determined using a dynamic planter aesthesiometer and weight bearing determined using an incapacitance tester. These behavioural measurements were taken before and after intra-articular AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100μg). Local administration of AYPGKF-NH(2) caused a significant increase in joint primary afferent firing rate and pain behaviour compared with the control peptide YAPGKF-NH(2). These effects were blocked by pretreatment with cromolyn. These data reveal that PAR(4) is expressed on synovial mast cells and the activation of PAR(4) has a pronociceptive effect that is dependent on mast cell activation. Proteinase-activated receptor-4 is expressed on synovial mast cells, and the activation of Proteinase-activated receptor-4 has a pronociceptive effect that is dependent on mast cell activation.
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http://dx.doi.org/10.1016/j.pain.2010.10.038DOI Listing
February 2011

Experience of gemcitabine plus oxaliplatin chemotherapy in patients with advanced biliary tract carcinoma.

Chemotherapy 2010 16;56(3):234-8. Epub 2010 Jun 16.

Department of Medical Oncology, University Hospital, Lille, France.

Backgrounds: The combination gemcitabine-oxaliplatin (GEMOX) is frequently used in patients with advanced biliary tract carcinoma (BTC). However, this is only based on phase II studies performed in selected patients.We assessed the efficacy and safety of the GEMOX regimen in non-selected patients with advanced BTC.

Methods: All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study: gemcitabine 1,000 mg/m(2) on day 1, and oxaliplatin 100 mg/m(2) on day 2, treatment repeated every 2 weeks until progression or unacceptable toxicity.

Results: Forty-four patients were enrolled.

Efficacy: 1 complete and 6 partial responses (objective response rate = 16.3%), 18 tumour stabilizations (41.9%, disease control rate = 58.1%), median progression-free survival was 5.0 months and median overall survival was 11.0 months.

Toxicity: grade 3 neuropathy in 4 patients, grade 3 asthenia in 5 patients.

Conclusion: The GEMOX combination was well tolerated, with a modest activity in non-selected patients with advanced BTC. This regimen should be compared to the new standard gemcitabine-cisplatin combination.
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http://dx.doi.org/10.1159/000316848DOI Listing
March 2011

Proteinase-activated receptor-2 up-regulation by Fcgamma-receptor activation in human neutrophils.

FASEB J 2010 Jun 12;24(6):2116-25. Epub 2010 Feb 12.

Centre de Recherche en Rhumatologie et Immunologie du Centre Hospitalier Universitaire de Québec, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Quebec, Canada.

We shed new light on the expression and function of the proteinase-activated receptor (PAR) family, associated with inflammation and hyperalgesia, in human granulocytes. Resting cells expressed constitutive levels of PAR-2 and PAR-3 mRNA but not PAR-1 or PAR-4. Based on flow cytometry, stimulation with opsonized bacteria (Bop) specifically up-regulated cell surface expression of PAR-2 in a concentration-dependent and time-dependent manner, independent of transcription or de novo protein synthesis. Primary granules were identified as a source of preformed PAR-2 that can readily be mobilized at the surface on fusion with the plasma membrane. Cellular response to PAR-2 activation, measured as changes in intracellular calcium concentration, was enhanced in PAR-2 up-regulated cells. Increase of cell-surface PAR-2 and of cell responsiveness were dependent specifically on the engagement of immunoglobulin (Ig)-binding receptors. Together, our results reveal that mobilization of intracellular granules, in response to Ig-receptor activation, up-regulates PAR-2 surface expression and makes neutrophils more responsive to proteinase activity. This enhanced response to PAR-2 activation indicates that molecular communication between pain and inflammation may be more important than previously believed.
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http://dx.doi.org/10.1096/fj.09-146167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881300PMC
June 2010

Beneficial influence of microsatellite instability on gelatinase-tissue inhibitors of metalloproteinase balance in colorectal cancer.

Anticancer Res 2007 Jan-Feb;27(1B):583-8

CHU Reims, Hôpital Robert Debré, Service d'Hépato-Gastroentérologie, Reims F-51092, France.

Background: Colorectal cancers (CRC) with high level of microsatellite instability (MSI-H) are characterized by lower metastasis propensity and better prognosis than their stable microsatellite (MSS) counterpart. It was hypothesized that the difference in cancer progression might be related to distinct gelatinase-tissue inhibitors of metalloproteinase (TIMPs) balance in MSI-H and MSS sporadic CRC.

Patients And Methods: Levels of gelatinase-A (MMP-2) and -B (MMP-9), TIMP-1 and -2 and membrane-type matrix metallo-proteinase-1 (MT1-MMP) were compared in tumors and normal mucosa from patients with MSI-H and MSS CRC.

Results: Active levels of MMP-2 and -9, normalized to normal mucosa, were lower in MSI-H than MSS CRC. There was a trend for higher levels of TIMP-1 and TIMP-2 within MSI-H tumors compared with MSS tumors (p=0.08 and p=0.15, respectively), while TIMP-2 amounts were significantly higher in adjacent normal tissue (p<0.001) in patients with MSI-H vs. MSS cancers. There was also a trend for lower MT1-MMP activity in MSI-H than in MSS CRC.

Conclusion: Our data suggest that the distinct invasive and metastatic behaviors of MSI-H and MSS CRC may be related to different patterns of gelatinase secretion and regulation.
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April 2007

Is there any relationship between pernicious anemia and iron deficiency?

Gastroenterol Clin Biol 2006 Nov;30(11):1245-9

Service d'Hépato-Gastro-Entérologie, CHU Robert Debré, Avenue du Général Koenig, 51092 Reims Cedex.

Introduction: Previous studies have suggested that iron deficiency could be due to atrophic gastritis of the body/fundus. The aim of this study was to determine the prevalence of iron deficiency among patients with pernicious anemia and associated factors.

Patients And Methods: All patients with pernicious anemia diagnosed at our institution between January 1990 and February 2005 were included. Inclusion criteria were: 1- histological diagnosis of atrophic fundic gastritis and 2- criteria of gastric autoimmune involvement. Histology of gastric biopsies was performed in a blinded manner. Iron deficiency was defined as serum ferritin level<15 microg/L in women and<40 microg/L in men.

Results: Ninety-five patients (69 women), mean age 60 years (range: 23-90) were included. Twenty patients (21.1%) had normal blood cell counts; 12 patients (12.6%) had microcytosis with or without anemia and 53 patients (55.8%) macrocytosis with or without anemia. Serum ferritin levels were measured in 58 patients, 16 (27.6%) of whom, all women, had iron deficiency. They were significantly younger (39.2 years) than patients without iron deficiency (61.6 years, P<0.0001). Serum gastrin levels did not differ between the groups with and without iron deficiency. A significantly more severe inflammatory infiltrate of the fundus and endocrine cell hyperplasia was observed in iron deficiency patients. Multivariate analysis showed that iron deficiency was linked to female gender and age<50 years.

Conclusion: Iron deficiency and microcytic anemia are not rare in patients with pernicious anemia and should not rule out the diagnosis. Iron deficiency does not appear to be related to the degree of atrophic fundic gastritis but is linked to female gender and young age, suggesting menstrual blood loss could play a role. Whether decreased iron absorption due to reduced acid secretion favors the expression of gynecological iron loss cannot be ascertained.
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http://dx.doi.org/10.1016/s0399-8320(06)73532-1DOI Listing
November 2006

[Stomach cancer].

Rev Prat 2005 Jan;55(2):123-30

Service d'hépato-qastro-entérologie, CHU Robert Debré, Avenue du Géneral Koenig, 51092 Reims, Courriel.

Despite its decline in incidence in developed countries, gastric cancer is the second digestive cancer in France and remains the second most cause of cancer-related deaths in the world. Gastritis induced by H. pylori infection and food regimen are the most frequent precancerous gastric factors. However there is no definite clinical evidence of the benefit of eradication on cancer risk. By waiting for effective anti-H. pylorivaccine, H. pylori should be only eradicated in selected patients at the highest risk of cancer. The stake is to develop inexpensive tests for identification of individuals at high risk, depending on genotypic polymorphisms of both the bacterium and the host. The endoscopic diagnosis is currently made at an advanced stage, related to non-specific and late symptoms. The prognosis remains poor with 5 years overall survival rate less than 20%. Surgical resection with D1 lymphadenectomy is the gold standard curative treatment. An adjuvant therapy with chemoradiotherapy should be considered for patients at high risk for recurrence. Gastric cancer is considered to be a chemotherapy sensitive disease, but polychemotherapy regimens (fluorouraci +/- cisplatin +/- epirubicin) result in modest increased survival (median 9 months); yet, the promising effectiveness of new drugs (irinotecan, docetaxel, oxaliplatin, capecitabin, targeted biotherapies) makes us hope an improvement of results. A number of entities, linitis plastica, gastric MALT lymphoma and stromal tumors should be recognised, because must have a different treatment.
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January 2005
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