Etude de progéniteurs rythroïdes normaux et pathologiques (signalisation et analyse protéomique)

L'Epo et la Tpo contrôlent l'hématopoïèse et agissent via les récepteurs EpoR et Mpl. La liaison Ligand-récepteur induit la phosphorylation et l'activation de Jak2, des récepteurs eux-mëmes et des voies STAT, MAPK et PI3-K. Nous montrons que les adaptateurs Gab interagissent avec Grb2, Shc, SHP2 en réponse à l'Epo et la Tpo et activent la PI3-K nécessaire au contrôle de l'apoptose, la prolifération et la différenciation. La PV est caractérisée par une hyperplasie érythroïde. Les mécanismes moléculaires responsables ne sont pas clairement identifiés. Les données actuelles suggèrent une anomalie de la signalisation Epo. A partir de cellules CD34+ médullaires humaines, nous obtenons une population homogène proche des CFU-E. L'analyse protéomique de patients et témoins a été réalisée par des techniques d'électrophorèse bidimensionnelle. Elle a permis d'établir une cartographie protéique et d'identifier 13 protéines différentielles, dont l'analyse en spectrométrie de masse est en cours.Epo and Tpo regulate hematopoiesis and act by the means of EpoR and Mpl receptor (R). Associating ligand-R induces tyrosine phosphorylation (YP) and activates Jak2, the receptors themselves and the STAT, MAPK and PI3-K pathways. We demonstrate that the Gab scaffold proeins medite EpoR, Mpl signaling and PI3-K activation. In UT7 and in primary hematopoietic cells, Gabs are YP in response to Epo and Tpo. They interact with Grb2, Shc, SHP2 and activate PI3-K pathway which is required for biological responses. PV is characterised by a erythroid hyperplasia. Original molecular mechanisms remain unclear. Data available suggest an abnormal EpoR signaling pathway. From human CD34+ BM cells, we obtain a homogeneous population conformed to CFU-E stage. Proteomic analysis of patients and healthy donors was performed with bidimensional electrophoresis assays. This enabled us to draw-up "a protein mapping" and identify differential spots which identification by mass spectrometry is under study.PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Place de la mutation JAK2 V617F et du test clonogénique dans le diagnostic de la polyglobulie de Vasquez et de la thrombocytémie essentielle : étude rétrospective d'une cohorte de patients explorés au CHU de Reims en 2006

REIMS-BU Santé (514542104) / SudocSudocFranceF

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

International audienceA 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

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

Abstract 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.</jats:p

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

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