23 research outputs found
Genomic approach of myeloproliferative neoplasms and relapsed large B-cell lymphoma
Lâoutil gĂ©nomique a considĂ©rablement modifiĂ© notre connaissance des hĂ©mopathies malignes, que ce soit sur le plan physiopathologique, diagnostique, pronostique ou thĂ©rapeutique. Dans la premiĂšre partie de ce travail, nous avons travaillĂ© sur une grande cohorte dâanĂ©mies rĂ©fractaires sidĂ©roblastiques avec thrombocytose (ARS-T). Nous avons dĂ©montrĂ© quâil sâagissait dâune entitĂ© indĂ©pendante, avec une prĂ©sentation molĂ©culaire particuliĂšre associant (i) des mutations de SF3B1 dans plus de 85% des cas, expliquant son versant myĂ©lodysplasique et (ii) des anomalies de JAK2 dans plus de 50% des cas, expliquant son versant prolifĂ©ratif. La perspective de cette premiĂšre partie est dâidentifier la ou les mutation(s) responsables du caractĂšre myĂ©loprolifĂ©ratif dans les ARS-T JAK2WT. Les lymphomes B-diffus Ă grandes cellules (LBDGC) reprĂ©sentent les lymphomes malins non-Hodgkiniens les plus frĂ©quents chez lâadulte. Dans la deuxiĂšme partie de ce travail, nous avons rĂ©alisĂ© lâanalyse par SNP-array dâune sĂ©rie homogĂšne dâĂ©chantillons issus de la cohorte CORAL, une Ă©tude prospective internationale portant sur les LBDGC en rechute. Notre objectif Ă©tait dâidentifier les anomalies de nombre de copies (ANC) associĂ©es Ă chacun des deux types de rechutes, prĂ©coces ou tardives. Les rechutes prĂ©coces sont associĂ©es Ă une forte proportion dâanomalies affectant les rĂ©gulateurs du cycle cellulaire, de lâapoptose et de la transcription. Les rechutes tardives sont associĂ©es Ă des anomalies affectant les rĂ©gulateurs de lâimmunitĂ© et de la prolifĂ©ration cellulaire. Cette Ă©tude permet de mieux comprendre les dĂ©terminants de la rechute dans les LBDGC et ouvre de nouvelles perspectives thĂ©rapeutiquesGenomics provided new insights in our knowledge of pathophysiology, diagnostic approach, prognosis and therapeutic perspectives in hematological malignancies. In the first part of this work, we studied a large cohort of Refractory Anemia with Ring sideroblasts and marked Thrombocytosis (RARS-T). We demonstrated that RARS-T can be considered as an independent entity, with a specific molecular pattern, associating : (i) SF3B1 mutations in more than 85% of cases, accounting for its myelodysplastic aspect and (ii) JAK2 mutations, accounting for its myeloproliferative aspect in more than 50% of cases. Future prospects of the first part of this work is to identify (the) mutation(s) responsible for the myeloproliferative part of JAK2WT RARS-T. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults. In the second part of this work, we performed SNP-array analysis of a homogeneous series of samples from the CORAL cohort, an international prognostic study on relapsed DLBCLs. Our purpose was to identify Copy Number Variations (CNV) associated ER or LR. ER DLBCLs are associated with high rates of CNVs affecting regulators of cell cycle, apoptosis and transcription. In LR DLBCLs, CNVs are related to immune response and cell proliferation. This study provides new insights into the genetic aberrations in relapsed DLBCLs and open up new therapeutic perspective
Approche génomique des syndromes myéloprolifératifs et des lymphomes B-diffus à grandes cellules en rechute
Genomics provided new insights in our knowledge of pathophysiology, diagnostic approach, prognosis and therapeutic perspectives in hematological malignancies. In the first part of this work, we studied a large cohort of Refractory Anemia with Ring sideroblasts and marked Thrombocytosis (RARS-T). We demonstrated that RARS-T can be considered as an independent entity, with a specific molecular pattern, associating : (i) SF3B1 mutations in more than 85% of cases, accounting for its myelodysplastic aspect and (ii) JAK2 mutations, accounting for its myeloproliferative aspect in more than 50% of cases. Future prospects of the first part of this work is to identify (the) mutation(s) responsible for the myeloproliferative part of JAK2WT RARS-T. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults. In the second part of this work, we performed SNP-array analysis of a homogeneous series of samples from the CORAL cohort, an international prognostic study on relapsed DLBCLs. Our purpose was to identify Copy Number Variations (CNV) associated ER or LR. ER DLBCLs are associated with high rates of CNVs affecting regulators of cell cycle, apoptosis and transcription. In LR DLBCLs, CNVs are related to immune response and cell proliferation. This study provides new insights into the genetic aberrations in relapsed DLBCLs and open up new therapeutic perspectivesLâoutil gĂ©nomique a considĂ©rablement modifiĂ© notre connaissance des hĂ©mopathies malignes, que ce soit sur le plan physiopathologique, diagnostique, pronostique ou thĂ©rapeutique. Dans la premiĂšre partie de ce travail, nous avons travaillĂ© sur une grande cohorte dâanĂ©mies rĂ©fractaires sidĂ©roblastiques avec thrombocytose (ARS-T). Nous avons dĂ©montrĂ© quâil sâagissait dâune entitĂ© indĂ©pendante, avec une prĂ©sentation molĂ©culaire particuliĂšre associant (i) des mutations de SF3B1 dans plus de 85% des cas, expliquant son versant myĂ©lodysplasique et (ii) des anomalies de JAK2 dans plus de 50% des cas, expliquant son versant prolifĂ©ratif. La perspective de cette premiĂšre partie est dâidentifier la ou les mutation(s) responsables du caractĂšre myĂ©loprolifĂ©ratif dans les ARS-T JAK2WT. Les lymphomes B-diffus Ă grandes cellules (LBDGC) reprĂ©sentent les lymphomes malins non-Hodgkiniens les plus frĂ©quents chez lâadulte. Dans la deuxiĂšme partie de ce travail, nous avons rĂ©alisĂ© lâanalyse par SNP-array dâune sĂ©rie homogĂšne dâĂ©chantillons issus de la cohorte CORAL, une Ă©tude prospective internationale portant sur les LBDGC en rechute. Notre objectif Ă©tait dâidentifier les anomalies de nombre de copies (ANC) associĂ©es Ă chacun des deux types de rechutes, prĂ©coces ou tardives. Les rechutes prĂ©coces sont associĂ©es Ă une forte proportion dâanomalies affectant les rĂ©gulateurs du cycle cellulaire, de lâapoptose et de la transcription. Les rechutes tardives sont associĂ©es Ă des anomalies affectant les rĂ©gulateurs de lâimmunitĂ© et de la prolifĂ©ration cellulaire. Cette Ă©tude permet de mieux comprendre les dĂ©terminants de la rechute dans les LBDGC et ouvre de nouvelles perspectives thĂ©rapeutique
Presence of calreticulin mutations in JAK2-negative polycythemia vera
International audienceCalreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)- and myeloproliferative leukemia (MPL)-negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2(V617F)-JAK2(exon12)-negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52-bp deletion. Single burst-forming units-erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV
Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease
Introduction: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry. Material and methods: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients. Results: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18â59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases. The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints. Conclusion: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition
Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome
International audienceIntroduction: Richter Syndrome (RS) is defined as the development of an aggressivelymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. Methods: We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. Results: Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-band IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral Blymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous butencouraging results. Conclusion: RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated
Higher Expression of CD44 in De Novo Diffuse Large B-cell Lymphoma Than in Richter Syndrome: USCAP 2022 Abstracts: Hematopathology (851-976)
Background: A subset of patients with chronic lymphocytic leukemia will experience transformation into Richter syndrome (RS), usually a diffuse large Bâcell lymphoma (DLBCL). Clonal relationship based on IGHV analysis can determine a true RStransformation. Separating de novo DLBCL and RS is essential because novo DLBCL have a significantly better prognosis. The aim of this study is to find differentially expressed proteins in RS and de novo DLBCL.Design: The study comprised a total of 44 samples, specifically 18 RS and 26 de novo DLBCL of the non-GCB type. Among the RS, 8 were clonally related, 2 were clonally unrelated and for 8 no information was available regarding the clonal relationship. Initial proteomic screening analysis was processed through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Among this 44 samples, 20 (10 RS and 10 de novo DLBCL) were analyzed by immunohistochemistry in order to evaluate the expression of CD44 and PKC-ÎČ. H-score was calculated with the semi quantitative evaluation of percentage of positive PKC-ÎČ cells multiplied by the weighted intensity of stain. All statistical analyses were performed using Studentâs t-test. A p < 0.05 was considered statistically significant.Results: LC-MS/MS proteomic study identified a panel of proteins differentially expressed between RS and de novo DLBCLs (FDR<0.05), including CD44 (which was comparatively underexpressed in RS) and PKC-ÎČ (which was comparatively overexpressed in RS). The immunohistochemical study confirmed that CD44 expression is significantly higher in de novo DLBCL than in RS (p<0.002). PKC-ÎČ is also overexpressed in RS, but the difference is not significant.Conclusions: RS has a very poor prognosis and should not be confused with de novo DLBCL. This study demonstrated the interest of CD44 to immunophenotically distinguish RS from de novo DLBCL
Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: Relevance to nonalcoholic liver disease
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Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses
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Serum albumin or body mass index: Which prognostic factor for survival in patients with acute myeloblastic leukaemia?
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