Publications by authors named "Antoine Ittel"

10 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

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

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

Triradial and quadriradial chromosomes detected in a case of B-cell prolymphocytic leukaemia.

Br J Haematol 2017 12 18;179(5):704. Epub 2017 Aug 18.

Département d'Onco-Hématologie, CHU de Hautepierre, Strasbourg, France.

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http://dx.doi.org/10.1111/bjh.14895DOI Listing
December 2017

Molecular combing: A new tool in diagnosing leukemia.

Cancer Biomark 2016 ;17(4):405-409

Département de Génétique Médicale, AP-HM La Timone, Marseille, France.

Background: According to the World Health Organization (WHO), recurrent cytogenetic abnormalities define many specific groups of hematopoietic tumors of acute myeloid and lymphoblastic leukemia, and these abnormalities are often strongly associated with prognosis and sometimes require specific treatments. These rearrangements are commonly detected by conventional and molecular cytogenetic techniques.

Objective: Using an alternative method, we sought to highlight the presence of chromosomal rearrangements.

Methods: We applied molecular combing to detect and directly visualize gene fusions associated with balanced translocations found in acute leukemia.

Results: In patients harboring t(12;21)(p13;q22), we demonstrated the presence of the fusion using specific probes covering the ETV6 and RUNX1 genes, with a positive result occurring due to the hybridization of the two probes to the same DNA fiber. Thanks to molecular combing, we also showed the presence of different breakpoints using these same probes.

Conclusions: Using several probes that are specific to the most common genes involved in acute leukemia, molecular combing could be an interesting additional tool in acute leukemia diagnosis.
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http://dx.doi.org/10.3233/CBM-160656DOI Listing
March 2017

Sumoylation Inhibits the Growth Suppressive Properties of Ikaros.

PLoS One 2016 17;11(6):e0157767. Epub 2016 Jun 17.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.

The Ikaros transcription factor is a tumor suppressor that is also important for lymphocyte development. How post-translational modifications influence Ikaros function remains partially understood. We show that Ikaros undergoes sumoylation in developing T cells that correspond to mono-, bi- or poly-sumoylation by SUMO1 and/or SUMO2/3 on three lysine residues (K58, K240 and K425). Sumoylation occurs in the nucleus and requires DNA binding by Ikaros. Sumoylated Ikaros is less effective than unsumoylated forms at inhibiting the expansion of murine leukemic cells, and Ikaros sumoylation is abundant in human B-cell acute lymphoblastic leukemic cells, but not in healthy peripheral blood leukocytes. Our results suggest that sumoylation may be important in modulating the tumor suppressor function of Ikaros.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912065PMC
July 2017

Increased risk of gestational vascular complications in women with low free tissue factor pathway inhibitor plasma levels out of pregnancy.

Thromb Haemost 2011 Jan 26;105(1):66-71. Epub 2010 Oct 26.

Department of Haematology, North University Hospital, Marseille, France.

Tissue factor pathway inhibitor (TFPI) plays a crucial role in haemostasis by regulating TF-induced initiation of coagulation. Since it is expressed by endothelial and trophoblastic cells, TFPI is of particular importance at the placental level and might be involved in the occurrence of gestational vascular complications (GVC). In the present study, we investigated plasma free TFPI antigen in four groups of women: healthy non-pregnant women without history of pregnancy complications; women at the beginning (<12 weeks) and women during the third trimester of a normal pregnancy; women with late pregnancy complications (pre-eclampsia / HELLP syndrome, intra-uterine fetal death, fetal growth retardation) at the time of obstetrical event and/or at distance from pregnancy. In normal pregnancy, TFPI increased between first trimester and delivery (median 5.0 ng/ml vs. 7.1 ng/ml; p<0.0001) but remained lower than in non-pregnant controls (median 8.2 ng/ml; p<0.0001). In patients, when measured concomitantly to the obstetrical event, TFPI showed no difference with normal late pregnancy levels. In contrast, at distance from pregnancy, in the absence of any hormonal influence, TFPI was significantly lower than in non-pregnant controls (median 5.9 vs. 8.2ng/ml, p < 0.0001). After categorisation into quartiles, an inverse dose-effect relationship was demonstrated between TFPI categories recorded apart from pregnancy and GVC risk, with a crude odds ratio of 43.5 (95% confidence interval 8.2-230) for patients with TFPI values in the lowest quartile (< 5.7 ng/ml). In conclusion, low free TFPI at distance from pregnancy appears to be a strong indicator of GVC risk.
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http://dx.doi.org/10.1160/TH10-06-0399DOI Listing
January 2011
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