Elizabeth Macintyre

Université Paris-Sorbonne - Paris IV, Lutetia Parisorum, Île-de-France, France

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Publications (82)710.44 Total impact

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    ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.
    Oncotarget 06/2015; · 6.63 Impact Factor
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    ABSTRACT: We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients younger than 66 years treated first-line with immuno-chemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age 56 years) was analyzed by multiplex ligation-dependent probe amplification (MLPA) and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). As expected, MYC (18%) was the more frequent gain, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%) and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A (p16), TP53, and CDKN1B (p27) were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (p16) (HR 2.3, p=0.007, adjusted for MIPI) and TP53 deletions (2.4, p=0.007), reflected in a dismal outcome with simultaneous deletions (median OS 1.8 years) compared to single deletions (4.3 and 5.1 years), or without these deletions (7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A (p16) and TP53 deletions were shown to be independent of the Ki-67 index. Despite immuno-chemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. The European MCL Younger trial is registered to www.clinicaltrials.gov as NCT00209222. Copyright © 2015 American Society of Hematology.
    Blood 05/2015; DOI:10.1182/blood-2015-02-628792 · 10.43 Impact Factor
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    ABSTRACT: Performance of methods used for molecular diagnostics must be closely controlled by regular analysis of internal quality controls. However, conditioning, shipping and long lasting storage of nucleic acid controls remain problematic. Therefore, we evaluated the minicapsules-based innovative process developed by Imagene (Evry, France) for implementing DNA and RNA controls designed for clonality assessment of lymphoproliferations and BCR-ABL1 mRNA quantification, respectively. DNA samples were extracted from 12 cell lines selected for giving specific amplifications with most BIOMED-2 PCR tubes. RNA samples were extracted from 8 cell line mixtures expressing various BCR-ABL1 transcript levels. DNA and RNA were encapsulated by Imagene and shipped at room temperature to participating laboratories. Biologists were asked to report quality data of recovered nucleic acids as well as PCR results. Encapsulated nucleic acids samples were easily and efficiently recovered from minicapsules. The expected rearrangements at immunoglobulin, T-cell receptor and BCL2 loci were detected in DNA samples by all laboratories. Quality of RNA was consistent between laboratories and met the criteria requested for quantification of BCR-ABL1 transcripts. Expression levels measured by the 5 laboratories were within±2 fold interval from the corresponding pre-encapsulation reference value. Moreover aging studies of encapsulated RNA simulating up to 100years storage at room temperature show no bias in quantitative outcome. Therefore, Imagene minicapsules are suitable for storage and distribution at room temperature of genetic material designed for proficiency control of molecular diagnostic methods based on end point or real-time quantitative PCR. Copyright © 2015. Published by Elsevier Inc.
    Clinical biochemistry 04/2015; DOI:10.1016/j.clinbiochem.2015.04.004 · 2.23 Impact Factor
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    ABSTRACT: T-cell acute lymphoblastic leukaemias (TALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 þ cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 þ T-ALLs. Sequencing reveals that 420% of monoallelic TAL1 þ patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5 0 to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.
    Nature Communications 01/2015; 6. DOI:10.1038/ncomms7094 · 10.74 Impact Factor
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    ABSTRACT: Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. © 2014 John Wiley & Sons Ltd.
    British Journal of Haematology 12/2014; DOI:10.1111/bjh.13272 · 4.96 Impact Factor
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    ABSTRACT: Background. Core binding factor (CBF) acute myeloid leukemia (AML) includes AML with t(8;21) and inv(16) leading to RUNX1-RUNX1T1 or CBFB-MYH11 fusion genes. These recurrent genetic abnormalities are both associated with disruption of genes encoding subunits of the CBF, a heterodimeric transcription factor involved in hematopoiesis. Although the fusion proteins appear to be crucial for the leukemogenic process, considerable experimental evidence indicates that they are not sufficient to induce AML on their own. Due to their high sensitivity to chemotherapy with high complete remission rates and their relatively favorable outcome, CBF-AML is considered to have a good prognosis. Nonetheless, about 30-40% of these patients relapse after standard intensive chemotherapy. In this context, identification of additional genetic or molecular abnormalities could allow better understanding of CBF-AML leukemogenesis, prediction of clinical outcome and identification of novel therapeutic targets. Methods. This study focuses on 73 patients with CBF-AML [43 t(8;21) and 30 inv(16)-AML] enrolled in the pediatric trial ELAM02. Single nucleotide polymorphism array (SNP-A) was performed for all patients using Cytoscan® HD arrays according to the manufacturer instructions. In order to distinguish somatic from constitutional SNP-A lesions, we excluded known copy number abnormalities (CNA) if there was textgreater50% overlap with variants from public database, except for breakpoints-related alterations. Interstitial uniparental disomies (UPD) textless10 Mb and telomeric UPD textless5 Mb were considered as constitutional and excluded from the analysis. Additionally, extensive mutational analysis (including 45 genes frequently reported to be mutated in myeloid malignancies) were performed for 37 and 25 patients with t(8;21) and inv(16)-AML respectively. Two different technologies of next generation sequencing (NGS) were used, allowing direct validation. Results. Among the 73 cases, 145 SNP-A lesions were found in 58 patients (81%) with a median of 2 lesions per case (range, 0-8). CNA was more frequent (84 losses, 47 gains) than UPD (n=14). No significant difference was noted between the number of CNA and UPD in inv(16) and t(8;21)-AML. Small lesions were common at breakpoints involved in the t(8;21) and inv(16) (respectively 4/43 and 6/30). Additional recurrent CNA mostly involved entire chromosomes, chromosomal arms or large chromosomal regions. Del(9q) and loss of sex chromosome were restricted to t(8;21)-AML (respectively 6/43 and 20/43). Trisomy 22 was restricted to inv(16)-AML (2/30). Other recurrent CNA included trisomy 8 (3/43 vs 1/30) and gains of 13q (2/43 vs 1/30) in both subtypes, gains of 1q and del(2q) in t(8;21)-AML (each 2/43). Del(7q) was among the most common aberrations regardless of subtype (7/43 and 7/30). The minimally deleted region of 7q contained 57 genes including MLL3 and EZH2. Additionally, we found focal deletions of IKZF1 in one patient, NF1 in another and 3 deletions of CCDC26. Except for known mutations (KIT, RAS, FLT3), NGS did not reveal any other alterations in inv(16)-AML. By contrast, t(8;21)-AML was marked by the frequency of mutations in ASXL1/2 (8%/24%) and cohesin genes SMC1A, SMC3, RAD21, STAG2, NIPBL (27% combined). Mutations were also detected in epigenetic-related genes EZH2 (5%), TET2 (8%), IDH1/2 (5%) and WT1(11%). Conclusions. SNP-A karyotyping of 73 pediatric CBF-AML revealed several recurrent alterations, with differing distribution between the 2 subgroups. Moreover, t(8;21) and inv(16)-AML appeared to have distinct mutational profiles, leading us to consider them separately for future studies. We recently reported high frequency of ASXL mutations in t(8;21)-AML and their absence in inv(16)-AML (Micol, Duployez and Boissel et al, Blood 2014). We now report high frequency of mutations in cohesin genes with the same distribution. Recent description of functional relations between cohesin and polycomb proteins, together with our results, suggest an important pathway in t(8;21) leukemogenesis. Concurrent ASXL and cohesin mutations were found in several patients, suggesting they could cooperate in some cases. Interestingly, ASXL mutations were exclusive of del(7q), suggesting that disruption of the ASXL-associated proteins MLL3 and EZH2 could be of great interest in the physiopathology of t(8;21)-AML. Finally, correlations with clinical outcome are in progress. Disclosures No relevant conflicts of interest to declare.
    12/2014; 124:1007-1007.
  • Blood 11/2014; 124(19):3023-5. DOI:10.1182/blood-2014-04-567636 · 10.43 Impact Factor
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    ABSTRACT: V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34(+)/CD1a(-)/CD7(+dim) stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct Dδ2-Jδ1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-δ gene assembly requires RUNX1 protein, which binds to the Dδ2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two Dδ gene segments in human TCR-δ chains. Absence of this RUNX1 binding site in the homologous mouse Dδ1-23RSS provides a molecular explanation for the lack of ordered TCR-δ gene assembly in mice and may underlie differences in early lymphoid differentiation between these species.
    Journal of Experimental Medicine 08/2014; 211(9):1821. DOI:10.1084/jem.20132585 · 13.91 Impact Factor
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    ABSTRACT: Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.
    PLoS ONE 07/2014; 9(7). DOI:10.1371/journal.pone.0103405 · 3.53 Impact Factor
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    ABSTRACT: Classification of acute myeloid leukemia (AML) has undergone dramatic changes with the introduction of the WHO classification in 2001. This classification attempts to categorize AML into 4 major categories on the basis of morphologic, immunophenotypic, genetic and clinical features. All categories present a good intra-group homogeneity except for the subgroup with 11q23/MLL abnormalities11q23 abnormalities are generally associated with unfavorable prognosis. More than 50 partners have been described for MLL, and 35 of these partners have been cloned and analysed at the molecular level. The specific functional role of each specific fusion transcript on the progression and outcome of disease remains to be elucidated to be effective at the clinical level. Such heterogeneity is a technical challenge at the diagnostic level. Current standard diagnostic testing for patients with acute leukemia includes cytogenetics backed up by FISH and/or RT-PCR. This screening strategy can be cumbersome in the clinical setting, since identification of the fusion gene partner may involve multiple and time-consuming analysis. We present here the results of an international multi-center study aimed at assessing the clinical performance of the MLL FusionChip™ kit, a molecular device designed to confirm the 11q23 abnormality and identify the MLL fusion gene partner. A previous study showed that the analytical performance of this oncodiagnostic device is compatible with its claimed use. In the current study, sample inclusion criteria were made on the basis of the current standard diagnosis procedures. Overall agreement between routine diagnostic analysis and the MLL FusionChip™ kit was > 90%. These results collectively suggest that the MLL FusionChip™ may be a clinically feasible oncodiagnostic device to improve acute leukemia stratification and enrich minimal residual disease (MRD) follow-up. Further consequences of enhanced patient stratification could lead to personalized therapy expansion, and to optimized use of molecular target-based therapeutics.
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    ABSTRACT: With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by Ig/TCR minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as primary endpoint. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with post-induction MRD level ≥ 10(-4) and unfavorable genetic characteristics (i.e. MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL; and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-ALL). These two factors allowed definition of a new risk classification, which is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL, not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and 2005 trials. Both trials were registered at ClinicalTrials.gov (GRAALL-2003, NCT00222027; GRAALL-2005, NCT00327678).
    Blood 04/2014; 123(24). DOI:10.1182/blood-2014-01-547695 · 10.43 Impact Factor
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    ABSTRACT: Although purine analogues have significantly improved the outcome of hairy cell leukaemia (HCL) patients, 30-40% relapse, illustrating the need for minimal residual disease (MRD) markers that can aid personalized therapeutic management. Diagnostic samples from 34 HCL patients were used to design an 8-colour flow cytometry (8-FC) tube for blood MRD (B/RD) analysis (188 samples) which was compared to quantitative IGH polymerase chain reaction (Q-PCR) on 83 samples and to qualitative consensus IGH PCR clonality analysis on 165 samples. Despite heterogeneous HCL phenotypes at diagnosis, discrimination from normal B lymphocytes was possible in all cases using a single 8-FC tube, with a robust sensitivity of detection of 10(-4) , comparable to Q-PCR at this level, but preferable in terms of informativeness, simplicity and cost. B/RD assessment of 15 patients achieving haematological complete remission after purine analogues was predictive of a clinically significant relapse risk: with a median follow-up of 95 months; only one of the nine patients with reproducible 8-FC B/RD levels below 10(-4) (B/RD(neg) ) relapsed, compared to 5/6 in the B/RD(pos) group (P = 0·003). These data demonstrate the clinical interest of a robust 8-FC HCL B/RD strategy that could become a surrogate biomarker for therapeutic stratification and new drug assessment, which should be evaluated prospectively.
    British Journal of Haematology 03/2014; 166(1). DOI:10.1111/bjh.12839 · 4.96 Impact Factor
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    ABSTRACT: Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3) .
    British Journal of Haematology 01/2014; 165(3). DOI:10.1111/bjh.12749 · 4.96 Impact Factor
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    ABSTRACT: The SET-NUP214 (TAF1/CAN) fusion gene resulting from either cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13)is a rare genetic event in T-cell acute lymphoblastic leukemia (T-ALL). Eleven of 196 (6%) T-ALLs enrolled in the French GRAALL-2003 and -2005 trials harbored a SET-NUP214 transcript. SET-NUP214 positive patients were predominantly (10/11; 91%) T-cell receptor (TCR) negative and strikingly associated to TCRγδ lineage T-ALLs, as defined by expression of a TCRγδ, or TCRδ and/or TCRγ rearrangements but no complete TCRβ VDJ rearrangement in surface CD3/TCR negative cases. When compared to SET-NUP214 negative patients, SET-NUP214+ cases showed a significantly higher rate of corticosteroid resistance (91% versus 44%; p=0.003) and chemoresistance (100% versus 44%; p=0.0001). All but one SET-NUP214+ patients achieved complete remission and nine were allografted. Despite the poor early treatment sensitivity, the outcome of SET-NUP214+ patients was similar to that of SET-NUP214-cases (p=0.52 for event-free survival and p=0.86 for overall survival). This trial is registered at clinicaltrials.gov, identifier: NCT00327678.
    Blood 01/2014; 123(12). DOI:10.1182/blood-2013-08-521518 · 10.43 Impact Factor
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    ABSTRACT: Little is known about intestinal CD4+ T-cell lymphoma; this rare malignancy is frequently misdiagnosed. We evaluated diagnostic criteria and factors that might affect its development and outcome. In a retrospective analysis, we analyzed medical records and intestinal specimens from 10 patients diagnosed with intestinal CD4+ T-cell lymphoma among 115 consecutive patients examined for severe enteropathy with villous atrophy. Samples were analyzed by histology, flow cytometry, and comparative genomic hybridization. Small intestine epithelial and lamina propria tissues from patients who presented with chronic diarrhea and malnutrition had variable levels of infiltration of the by CD3+ CD4+ T cells. Flow cytometry revealed a high frequency of CD4+ intra-epithelial cells, which frequently expressed a specific Vβ chain. T-cell receptor β clonality was confirmed by DNA sequencing. Two patients had HLA and serology results compatible with celiac disease and autoimmune enteropathy, respectively. Two patients were found to have antibodies against human T-cell leukemia virus and 2 patients had signs of recent infection with herpes viruses. Comparative genomic hybridization analyses showed heterogeneous chromosomal abnormalities. Symptoms were reduced in patients treated with steroids (n=5), but not in patients given purine analogues or chemotherapy. Antibodies against CD52 produced clinical and histological responses in 2/2 patients, whereas severe adverse effects developed in 1 patient. At the latest follow up, all patients are alive. There is much heterogeneity in onset and genetic features of intestinal CD4+ T cell lymphomas, despite their common presentation as indolent lymphoproliferations of the intestinal mucosa. Patients should be treated with steroids, and possibly antibodies against CD52 (for the most aggressive forms of this disorder).
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; 12(4). DOI:10.1016/j.cgh.2013.11.028 · 6.53 Impact Factor
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    ABSTRACT: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
    Journal of Clinical Oncology 10/2013; 31(34). DOI:10.1200/JCO.2012.48.5292 · 18.43 Impact Factor
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    ABSTRACT: Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (±34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4-97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9-88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse.
    Medicine 08/2013; 92(5). DOI:10.1097/MD.0b013e3182a71eba · 4.87 Impact Factor
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    ABSTRACT: CALM-AF10 (also known as PICALM-MLLT10) is the commonest fusion protein in T-cell acute lymphoblastic leukemia, but its prognostic impact remains unclear. Molecular screening at diagnosis identified CALM-AF10 in 30/431 (7%) T-cell acute lymphoblastic leukemia patients aged 16 years and over and 15/234 (6%) in those aged up to 15 years. CALM-AF10 positive patients were predominantly (72%) surface (s)CD3/T-cell receptor negative in adults, but predominantly (67%) T-cell receptor positive in children. Amongst 22 adult CALM-AF10+ patients treated according to the LALA94/GRAALL03-05 protocols, the poor prognosis for event-free survival (p=0.0017) and overall survival (p=0.0014) was restricted to the 15 T-cell receptor negative cases. Amongst CALM-AF10+ T-cell receptor negative patients, 82% demonstrated an early T-cell precursor phenotype, reported to be of poor prognosis in pediatric T-cell acute lymphoblastic leukemia. Early T-cell precursor acute lymphoblastic leukemia corresponded to 22% of adult LALA94/GRAALL03-05 T-cell acute lymphoblastic leukemias, but had no prognostic impact per se. CALM-AF10 fusion within early T-cell precursor acute lymphoblastic leukemia (21%) did, however, identify a poor prognostic group for event-free survival (p=0.04). CALM-AF10 therefore identifies a poor prognostic group within sCD3/T-cell receptor negative adult T-cell acute lymphoblastic leukemias and is over-represented within early T-cell precursor acute lymphoblastic leukemias, where it identifies those likely to fail treatment. Its prognosis and overlap with early T-cell precursor acute lymphoblastic leukemia in pediatric T-cell acute lymphoblastic leukemia merits analysis. The clinical trial GRAALL was registered at Clinical Trials.gov number NCT00327678.
    Haematologica 07/2013; DOI:10.3324/haematol.2013.086082 · 5.87 Impact Factor
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    ABSTRACT: Bone marrow flow cytometric analysis is a powerful and rapid tool for evaluating aberrant plasma cell. In this study, we have examined the utility of multiparameter flow cytometry (MFC) in 52 patients with multiple myeloma (MM) and in 45 patients with monoclonal gammopathy with unknown significance (MGUS) into routine evaluation for the management of patients with plasma cell-related disorders. The plasma cells (PC) were identified by their light scatter distribution and reactivity patterns to CD138, CD38, and CD45. The combination of these parameters was helpful for identifying distinct subpopulations of PCs. Moderate to bright expression of CD56, CD20, CD24, CD28, and CD117 was detected in 67%, 26%, 13%, 27%, and 57% of MM cases and in 58%, 20%, 11%, 43% and 44% of MGUS cases, respectively. In MGUS group, the median percentage abnormal PCs/total PCs was 88% with 37 patients out of 45 (82%) with ratio <95%. The median ratio of the MM group was 98.9% and a ratio ≥ 95% was observed in 37 samples out of 44 (84%). In conclusion, MFC immunophenotyping of PCs has obvious clinical relevance in differential diagnosis between MM and others monoclonal gammopathies, identification of high-risk MGUS and smouldering MM, and minimal residual disease monitoring of MM. Our results showed that this tool can be easily applied in haematology laboratories.
    06/2013; 71(3):313-323. DOI:10.1684/abc.2013.0813

Publication Stats

3k Citations
710.44 Total Impact Points

Institutions

  • 2013–2015
    • Université Paris-Sorbonne - Paris IV
      Lutetia Parisorum, Île-de-France, France
  • 2014
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 2000–2014
    • Université René Descartes - Paris 5
      • • Faculty of medicine
      • • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Université de Vincennes - Paris 8
      Saint-Denis, Île-de-France, France
  • 2000–2011
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2005–2009
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
  • 2008
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2007
    • Cliniques Universitaires Saint-Luc
      • Division of Hematology
      Bruxelles, Brussels Capital Region, Belgium
  • 2003
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France