Publications by authors named "Christine Lefebvre"

62 Publications

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

Myeloid malignancies with translocation t(4;12)(q11-13;p13): molecular landscape, clonal hierarchy and clinical outcomes.

J Cell Mol Med 2021 Oct 7;25(20):9557-9566. Epub 2021 Sep 7.

Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Paris, France.

Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
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http://dx.doi.org/10.1111/jcmm.16895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505829PMC
October 2021

c-MYC and p53 expression highlight starry-sky pattern as a favourable prognostic feature in R-CHOP-treated diffuse large B-cell lymphoma.

J Pathol Clin Res 2021 Nov 9;7(6):604-615. Epub 2021 Aug 9.

Department of Pathology, Grenoble-Alpes University Hospital, Grenoble, France.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous entity, in which the first-line treatment currently consists of an immuno-chemotherapy regimen (R-CHOP). However, around 30% of patients will not respond or will relapse. Overexpression of c-MYC or p53 is frequently found in DLBCL, but an association with prognosis remains controversial, as for other biomarkers previously linked with DLBCL aggressivity (CD5, CD23, or BCL2). The aim of this study was to explore the expression of these biomarkers and their correlation with outcome, clinical, or pathological features in a DLBCL cohort. Immunohistochemical (c-MYC, p53, BCL2, CD5, and CD23), morphological ('starry-sky' pattern [SSP]), targeted gene panel sequencing by next-generation sequencing (NGS), and fluorescence in situ hybridisation analyses were performed on tissue microarray blocks for a retrospective cohort of 94 R-CHOP-treated de novo DLBCL. In univariate analyses, p53 overexpression (p53 ) was associated with unfavourable outcome (p = 0.04) and with c-MYC overexpression (p = 0.01), whereas c-MYC overexpression was linked with an SSP (p = 0.004), but only tended towards an inferior prognosis (p = 0.06). Presence of a starry-sky morphology was found to be correlated with better survival in p53 DLBCL (p = 0.03) and/or c-MYC-positive DLBCL (p = 0.002). Furthermore, NGS data revealed that these three variables were associated with somatic mutations (PIM1, TNFRSF14, FOXO1, and B2M) involved in B-cell proliferation, survival, metabolism, and immune signalling. Taken together, these results show that the SSP pattern seems to be a protective factor in high-risk DLBCL subgroups and highlight cell death as a built-in failsafe mechanism to control tumour growth.
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http://dx.doi.org/10.1002/cjp2.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503894PMC
November 2021

Adverse outcome in follicular lymphoma is associated with MYC rearrangements but not MYC extra copies.

Br J Haematol 2021 Jul 21;194(2):382-392. Epub 2021 Jun 21.

Department of Hematology, Grenoble-Alpes University Hospital, Grenoble, France.

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and β2-microglobulin (β2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome.
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http://dx.doi.org/10.1111/bjh.17550DOI Listing
July 2021

Thoracic NUT carcinoma: Common pathological features despite diversity of clinical presentations.

Lung Cancer 2021 08 8;158:55-59. Epub 2021 Jun 8.

CHU Grenoble-Alpes, Department of Pathology, 38043, Grenoble, France; Univ Grenoble Alpes, CNRS UMR5309, Inserm U1209, Institute for Advanced Biosciences, F-38000, Grenoble, France. Electronic address:

NUT carcinoma (NC), formerly known as NUT midline carcinoma, is a rare and very aggressive cancer. It is genetically defined by the presence of acquired chromosomal rearrangement of the NUTM1 (NUclear protein in Testis Midline carcinoma family member 1) gene at chromosome 15q14 with a member of the bromodomain-containing protein (BRD) family gene, usually BRD4. Although primarily reported in the head and neck, and mediastinum locations of younger individuals, it is now established that NC arises in multiple sites in patients of all ages, with no gender predilection. NC is very likely to be underdiagnosed because of a lack of awareness of both clinicians and pathologists on the one hand, and of a nonspecific histological presentation on the other hand. As it is indistinguishable from other poorly differentiated carcinomas, pathologists should consider NC as a differential diagnosis of any poorly differentiated tumour. Diagnosis is now easily made by immunohistochemistry, using a highly sensitive and specific NUT monoclonal antibody. Despite chemo- or chemo-radiotherapy, the prognosis of this tumour remains very poor. We report here a series of 3 cases of NC with different clinical and pathological presentations in order to draw attention on some common morphological features that can help clinicians and pathologists to think about this rare entity.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.008DOI Listing
August 2021

Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming.

J Clin Invest 2021 07;131(13)

INSERM U1111, CNRS UMR 5308, Centre International de Recherche en Infectiologie, Lyon, France.

Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
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http://dx.doi.org/10.1172/JCI139675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245185PMC
July 2021

Dramatic Efficacy of Ibrutinib in a Schnitzler Syndrome Case with Indolent Lymphoma.

J Clin Immunol 2021 Aug 19;41(6):1380-1383. Epub 2021 Apr 19.

Hematology Department, University Hospital of Grenoble, La Tronche, France.

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http://dx.doi.org/10.1007/s10875-021-01038-yDOI Listing
August 2021

Using Prevent Teach Reinforce for Young Children to Manage Challenging Behaviors in Public Specialized Early Intervention Services for Autism.

J Autism Dev Disord 2021 Nov 9;51(11):3970-3988. Epub 2021 Jan 9.

Departement of Psychoéducation, Université de Sherbrooke, Sherbrooke, QC, Canada.

This proof-of-concept study assessed the feasibility of implementing Prevent-Teach-Reinforce-for-Young-Children (PTR-YC) program to address challenging behaviors in children with autism within the context of public, specialized early intensive behavioral intervention (EIBI) services offered in community settings. Following a 2-day training and with brief weekly supervision meetings, children's EIBI educators acted as facilitators in 35 families' home environments. Small and moderate effect sizes were observed for children's behavioral outcomes and parenting stress. Recruitment and retention rates, implementation fidelity, as well as treatment acceptability from the perspective of participating parents and the organization attested to the feasibility and relevance of implementing and evaluating this program on a larger scale as part of a multi-center randomized controlled trial.
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http://dx.doi.org/10.1007/s10803-020-04856-yDOI Listing
November 2021

Interhemispheric differences in P1 and N1 amplitude in EEG and MEG differ across older individuals with a concussion compared with age-matched controls.

Psychophysiology 2021 03 21;58(3):e13751. Epub 2020 Dec 21.

Department of Psychology, Université de Montréal, Montréal, QC, Canada.

We studied the effects of mild traumatic brain injury (mTBI) in an aging population. We examined visual search with event-related potentials (ERPs) and event-related fields (ERF) for a lateral color singleton focusing on the P1 and N1 in each hemisphere. Forty participants (19 mTBI and 21 controls) aged 50 to 72 performed a visual search task, while we recorded their magnetoencephalogram (MEG) with simultaneous electroencephalogram (EEG). We compared visual ERPs and ERFs and associated cortical activity estimated using MEG source localization. Relative to matched controls, participants with an mTBI had a smaller P1 in the left hemisphere and a smaller N1 in the right hemisphere. Also, mTBI participants showed inversed activation patterns across the hemispheres during the N1 in MEG compared with controls. This is the first study to investigate the impact of mTBI on neuronal source activations during early visual processing in an aging population. Results showed that when aging individuals suffer from an mTBI, there are perturbations in the amplitude and hemispheric dominance patterns in the visual P1 and N1 responses that are visible for months to years following the injury. Our findings indicate that mTBI can lead to modifications of sensory and/or perceptual responses, suggesting possible adaptive functional reorganization following mTBI.
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http://dx.doi.org/10.1111/psyp.13751DOI Listing
March 2021

Signal informativeness for sequence structure modulates human auditory cortical responses.

Psychophysiology 2021 03 14;58(3):e13745. Epub 2020 Dec 14.

Département de psychologie, Université de Montréal, Montréal, QC, Canada.

We observed how information about the structure of tone sequences modulates cortical responses in the context of a standard short-term memory (STM) task. Participants heard two sequences of one, three, or five tones (203 ms on, 203 ms off) interspersed by a silent interval (2 s) and decided whether the sequences were the same or different. In experiment 1, sequence length was randomized between trials. During the first sequence, the amplitude of the auditory P2 was larger for the second tone in trials with three tones, and for the second and fourth tone in trials with five tones. We hypothesize the increase in P2 reflected a dynamic disambiguation process because these tones were predictive of a sequence longer than one or three tones. This hypothesis was supported by the absence of P2 amplitude modulation during the second sequence (when sequence length was known). In experiment 2, we blocked trials by sequence length to ensure the effects were not caused by some process related to encoding in STM. There was no P2 amplitude modulation in either the first or second sequences. Thus, tones 2 and 4 had a larger amplitude only when they provided new information about the length of the current tone sequence. To some extent, the auditory N1 also showed those modulations. Independent Component Analysis of the ERPs provided evidence the modulations in P2 amplitude could originate in auditory cortex. These results suggest a rapid dynamic adaptation of auditory cortical responses based on the local informativeness of auditory signals.
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http://dx.doi.org/10.1111/psyp.13745DOI Listing
March 2021

Clinical and biological features of B-cell neoplasms with CDK6 translocations: an association with a subgroup of splenic marginal zone lymphomas displaying frequent CD5 expression, prolymphocytic cells, and TP53 abnormalities.

Br J Haematol 2021 04 13;193(1):72-82. Epub 2020 Dec 13.

Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.

A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.
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http://dx.doi.org/10.1111/bjh.17141DOI Listing
April 2021

Transformation of a low-grade follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing Terminal deoxynucleotidyl Transferase: a case report.

J Med Case Rep 2020 Jul 27;14(1):117. Epub 2020 Jul 27.

Department of Pathology, CHU de Grenoble, Grenoble, France.

Background: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 is an aggressive mature B-cell neoplasm, whereas B-lymphoblastic lymphoma is immature cell proliferation, with a frequent positivity for terminal deoxynucleotidyl transferase. The transformation of a low-grade follicular lymphoma into a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase is a very rare event.

Case Presentation: A 55-year-old Caucasian man was followed for a grade 1-2 follicular lymphoma carrying a t(14;18) IGH/BCL2+ and was initially treated with R-CHOP. The follicular lymphoma presented two relapses. In the third relapse, the patient had multiple lymphadenopathy and ascites, which motivated a retroperitoneal biopsy and an ascitic tap. These samples were analyzed by histological, cytological, flow cytometric, cytogenetic, and molecular assessments. The patient died of a multiple organ dysfunction syndrome 2 weeks after his third relapse. The biopsy revealed a diffuse proliferation made up of two types of tumor cells: centroblasts (Bcl-6-positive) and immature cells (terminal deoxynucleotidyl transferase-positive). Flow cytometric analysis confirmed the immature phenotype, with an expression of terminal deoxynucleotidyl transferase, combined with a loss of membrane immunoglobulins. The cytogenetic analysis performed on the ascites revealed a clonal evolution characterized by a t(8;22)(q24;q11) MYC+ translocation not previously detected in follicular lymphoma. Fluorescence in situ hybridization confirmed the double rearrangement of the BCL2 and MYC genes. Polymerase chain reactions and sequencing were used to study the clonal relationship between follicular lymphoma and the secondary tumors. The IGVH gene rearrangement revealed a unique clonal rearrangement involving an IGVH4-59 subset in all three specimens.

Conclusion: These findings suggest a clonal relationship between the two types of lymphoma cells. Furthermore, they support the transformation of an acute follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase. This case report highlights the possible transformation of follicular lymphoma into a highly aggressive and immature proliferation.
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http://dx.doi.org/10.1186/s13256-020-02433-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384216PMC
July 2020

Development of a questionnaire to assess the quality of service trajectories in autism spectrum disorder from families' perspective.

J Appl Res Intellect Disabil 2020 Nov 6;33(6):1500-1511. Epub 2020 Jul 6.

Department of Psychology, Université du Québec à Montréal, Montréal, QC, Canada.

Background: ETAP-1 was created to evaluate the quality of services trajectory from families' perspective. The items of ETAP-1 were developed from previous studies on integrated care, existing quality assessments, and consultations with families and experts in evaluation and in autism spectrum disorder (ASD).

Method: The questionnaire was completed by 200 parents of children aged 5 and under who were recently diagnosed with ASD or intellectual disability. Of these, 183 received diagnostic evaluation through a clinic specialized in ASD; the other 17 underwent diagnostic evaluation in hospital settings.

Results: Factor analysis supported the a priori dimensions of quality and distinctions between experiences before and during diagnostic evaluation. The instrument had high internal consistency, convergent and discriminant validity with other measures and was sensitive to differences in service delivery models.

Discussion: ETAP-1 is useful in organizing information on families' experiences throughout their services trajectories and according to a dynamic perspective.
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http://dx.doi.org/10.1111/jar.12777DOI Listing
November 2020

Increased S100A8 expression in bone marrow plasma by monocytic cells from acute myeloid leukemia patients.

Hematol Oncol 2020 Feb 6;38(1):114-118. Epub 2020 Jan 6.

Institute for Advanced Biosciences, University Grenoble Alpes /INSERM U1209/CNRS 5309, Grenoble, France.

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http://dx.doi.org/10.1002/hon.2707DOI Listing
February 2020

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blood Adv 2019 12;3(24):4238-4251

Laboratoire d'Hématologie, CHU Estaing 1, Clermont-Ferrand, France.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.
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http://dx.doi.org/10.1182/bloodadvances.2019000647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929390PMC
December 2019

Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.

Blood 2019 11;134(21):1821-1831

Service de Génétique Biologique-Histologie, CHU Besançon, Besançon, France.

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
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http://dx.doi.org/10.1182/blood.2019001187DOI Listing
November 2019

A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

Cancers (Basel) 2018 Dec 21;11(1). Epub 2018 Dec 21.

Unit Nutritional and Hormonal Biochemistry, Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, 38043 Grenoble CEDEX 9, France.

Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM.
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http://dx.doi.org/10.3390/cancers11010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356827PMC
December 2018

Poor prognosis of chromosome 7 clonal aberrations in Philadelphia-negative metaphases and relevance of potential underlying myelodysplastic features in chronic myeloid leukemia.

Haematologica 2019 06 20;104(6):1150-1155. Epub 2018 Dec 20.

Département d'Hématologie, Institut Bergonié, Bordeaux, France.

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.
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http://dx.doi.org/10.3324/haematol.2018.208801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545846PMC
June 2019

Testing between the gunpowder fuse and the filling-hose analogy for mental curve tracing using electroencephalography: boom!

Neuroreport 2018 12;29(17):1437-1442

Centre de recherche de l'Institut Universitaire de Gériatrie de Montréal.

Curve tracing occurs when a line is followed covertly to accomplish a task, for example, to determine whether two landmarks are on the same line or not (could Highway 61 take Robert Johnson from New Orleans to St Louis?). Previous work suggests that attention either moves along the curve, momentarily activating local representations of the curve during this process, leaving little or no trace of this activation once attention has passed, or attention spreads along the curve, resulting in an activated state along the entire portion of the curve that was traced. We re-examined this issue using event-related potentials. Curves to be traced were presented briefly to encourage a rapid deployment of attention. The curves started on the vertical midline and passed into the left or right visual field and terminated either on the vertical midline or at a lateral position. We measured a posterior contralateral negativity (relative to the visual field of the traced curve) that offset more rapidly when the curve was traced back to the midline than when it remained lateral. The results suggest that attention travels along the curve like fire on a fuse, with activation returning to baseline once the flame has passed.
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http://dx.doi.org/10.1097/WNR.0000000000001114DOI Listing
December 2018

Molecular dissection of engraftment in a xenograft model of myelodysplastic syndromes.

Oncotarget 2018 Mar 20;9(19):14993-15000. Epub 2018 Feb 20.

University Clinic of Hematology, CHU Grenoble Alpes, Grenoble, France.

Myelodysplastic syndromes (MDS) are oligoclonal disorders of the hematopoietic stem cells (HSC). Recurrent gene mutations are involved in the MDS physiopathology along with the medullar microenvironment. To better study the heterogeneity of MDS, it is necessary to create patient derived xenograft (PDX). We have reproduced a PDX model by xenografting HSC (CD34) and mesenchymal stromal cells (MSC) in NOD/SCID/IL2rγ mice with primary samples from one RAEB2, two RAEB1 and one RARS patients harboring karyotype abnormalities and gene mutations. The average human chimerisms ranged from 59.7% to 0.0175% for the 4 patients. Secondary grafts (G2) were only performed for mice derived from the RAEB2 patient and the average human chimerism was 53.33%. G1 mice 1 and 2, and their derived G2 mice showed less than 20% of medullar blasts whereas mouse 3 and the resulting G2 mice transformed to AML. Clonal architecture was dissected in the different hematopoietic progenitors (HP) harvested from G1 and G2 mice. By direct Sanger sequencing, we found the 4 initial mutations in each HP subpopulation and those mutations had the same variant allele frequency in the CD34 CD38 HSC from G1 and G2 mice by next generation sequencing (NGS). Targeted NGS analysis done in HSC of mouse 3 did not show any additional driver gene mutations explaining the transformation to AML. To conclude, we have generated a PDX mouse model that perfectly reproduces the MDS founder clone which is stable over time, allowing us to consider this system as a powerful tool to test therapeutic approaches.
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http://dx.doi.org/10.18632/oncotarget.24538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871091PMC
March 2018

Reactive oxygen species levels control NF-κB activation by low dose deferasirox in erythroid progenitors of low risk myelodysplastic syndromes.

Oncotarget 2017 Dec 6;8(62):105510-105524. Epub 2017 Nov 6.

CHU Grenoble Alpes, University Clinic of Hematology, Grenoble, France.

Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3μM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-κB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-κB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-κB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents.
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http://dx.doi.org/10.18632/oncotarget.22299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739655PMC
December 2017

"Double-hit" chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain.

Am J Hematol 2018 03 18;93(3):375-382. Epub 2017 Dec 18.

INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.

Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.
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http://dx.doi.org/10.1002/ajh.24990DOI Listing
March 2018

Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.

Blood 2017 10 8;130(16):1832-1844. Epub 2017 Aug 8.

Department of Hematology, University Hospital Saint-Louis, AP-HP, University Paris Diderot, Paris, France.

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ and 14q32/ translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.
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http://dx.doi.org/10.1182/blood-2017-05-783852DOI Listing
October 2017

Backward masking interrupts spatial attention, slows downstream processing, and limits conscious perception.

Conscious Cogn 2017 09 11;54:101-113. Epub 2017 Apr 11.

Centre de Recherche en Neuropsychologie et Cognition, Department of Psychology, Université de Montréal, CP 6128 Succursale Centre-ville, Montréal, Québec H3C 3J7, Canada.

The attentional blink (AB) is a difficulty in correctly processing a target when it follows one or more other targets after a short delay. When no backward mask is presented after the last critical target, there is no or little behavioral AB deficit. The mask plays an important role in limiting conscious access to target information. In this electrophysiological study, we tested the impact of masking on the deployment and engagement of attention by measuring the N2pc and P3 components in an RSVP paradigm. We found that the presence of a mask in an AB paradigm reduced the amplitude of the N2pc, P3a, and P3b components. In addition to reducing encoding in memory, masking also reduced the effectiveness of the deployment and engagement of attention on the last target. We discuss the role of these findings in the context of current masking, consciousness, and AB models.
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http://dx.doi.org/10.1016/j.concog.2017.04.005DOI Listing
September 2017

Cytogenetics in the management of lymphomas and lymphoproliferative disorders in adults and children: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

Ann Biol Clin (Paris) 2016 Oct;74(5):568-587

Centre de génétique humaine, Cliniques universitaires St-Luc & de Duve Institute - Université catholique de Louvain, Bruxelles, Belgique.

Non-Hodgkin's lymphomas and lymphoproliferative disorders include a high number of heterogeneous entities, described in the 2008 WHO classification. This classification reflects the crucial role of a multidisciplinary approach which integrates cytogenetic results both for the notion of clonality and for differential diagnosis between these entities. The prognostic impact of some cytogenetic abnormalities or genome complexity is also confirmed for many of these entities. Novel provisional entities have been described, such as BCLU (B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) for which karyotype is critical to distinguish BCLU from Burkitt's lymphoma. The karyotype can be established from any tumour or liquid infiltrated by lymphoma cells. Recent adaptations of technics for cellular cultures according to the subtype of known (or suspected) lymphoma have significantly improved the percentage of informative karyotypes. Conventional karyotypes remain the best technical approach recommended for most of these subtypes. Interphase and/or metaphase FISH also represents a solid and rapid approach, because of the significant number of recurrent (sometimes specific) rearrangements of these entities. Next generation sequencing technologies contribute to enrich genomic data and substantially improve the understanding of oncogenic mechanisms underlying these lymphoid malignancies. Some molecular biomarkers are already part of the diagnostic process (for example, somatic mutation of MYD88 in Waldenström disease) thus reinforcing the essential principle of a multidisciplinary approach for the diagnosis of all the mature lymphoid malignancies.
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http://dx.doi.org/10.1684/abc.2016.1179DOI Listing
October 2016

Cytogenetics in the management of children and adult acute lymphoblastic leukemia (ALL): an update by the Groupe francophone de cytogénétique hématologique (GFCH).

Ann Biol Clin (Paris) 2016 Oct;74(5):547-560

Laboratoire de cytogénétique onco-hématologique, Hôpital Timone enfants, APHM, Marseille, France; Inserm U1104, Aix-Marseille Université, Marseille, France.

Cytogenetic analyses (karyotype and, if necessary, appropriate complementary FISH analyses) are mandatory at diagnosis in acute lymphoblastic leukemia (ALL) as their results are taken into account in therapeutic protocols due to their diagnostic and prognostic values. In some cases, karyotype can be completed by other techniques (RT-PCR, RQ-PCR, DNA content, SNP-array, MLPA…) that can be equally or more informative than FISH. Here, we have tempted to establish guidelines concerning karyotype and FISH analyses according to the most recent data of the litterature which is reviewed here, completing the 2008 WHO classification with the recent new cytogenomic entities such as Ph-like ALL and indicating possible therapeutic implications.
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http://dx.doi.org/10.1684/abc.2016.1176DOI Listing
October 2016
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