Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

International audiencePrimary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF

Haematologica

Not available

Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial

Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373)

Myeloproliferative neoplasms and thromboses : epidemiology and identification of thrombotic risk factors

Les néoplasies myéloprolifératives (NMP) sont des hémopathies myéloïdes clonales, chroniques et prolifératives. Les plus fréquentes sont la polyglobulie de Vaquez et la thrombocytémie essentielle. Elles s’accompagnent de risques importants de thrombose (artérielles et veineuses) et de transformation en pathologies plus agressives (myélofibrose secondaire et leucémie aigüe). Les thromboses peuvent être la situation diagnostique de ces maladies, ou survenir au cours de la prise en charge. Le sujet de cette thèse est d’étudier la relation clinique entre NMP et thrombose. Dans un contexte de survenue de thrombose veineuse idiopathique, sans antécédent NMP, nous nous sommes intéressés à la recherche de mutation clonale chez les patients comme moyen diagnostique d’une NMP. Nous avons ainsi exploité la cohorte EDITH du CIC en prenant les patients ayant expérimentés un puis une récurrence thrombotique. A l’inverse, nous avons constitué une base de données (OBENE) des patients pris en charge pour une NMP au CHRU de Brest.Nous avons ensuite exploité cette base, en analysant la fréquence et l’impact des arythmies cardiaques auriculaires, la balance bénéfice-risque à l’utilisation des NACO, l’impact des statines sur la réduction du risque de thrombose ainsi que la fréquence et l’impact de la nonadhérence aux traitements dans les PV et TE.NMP et thromboses sont liées, il est donc nécessaire d’approfondir les connaissances de leur physiopathologie spécifique pour améliorer la prévention et le traitement des épisodes. Cette thèse amène quelques réponses àcertaines questions mais elle est surtout le point de départ de réflexion commune entre les praticiens et biologistes intéressés par ces domaines.The myeloproliferative neoplasms (MPN) are clonal myeloid, chronic and proliferative disorders. The most frequent are polycythemia vera and essential thrombocythemia. The more frequent complications are thromboses (arterial and venous) and phenotypic evolutions (secondary myelofibrosis and acute leukemia). Thromboses can be a situation of diagnosis or observed during the followup of a MPN. This thesis is focused on the clinical link between MPN and thromboses.In a context of idiopathic venous thromboses (first event or recurrence), without medical history of MPN, we have tested patients for the most frequent MPN clonal mutations. So, we have used the informations and patients of the dedicated EDITH cohort.On the other hand, we have constituted a MPN database (OBENE) of the patients diagnosed for MPN in our Hospitalcentre. By this way, we have analysed the frequency and impact of atrial arrhythmias, the benefit-risk balance of the use of DOAC, the impact of statins to reduce the thrombotic risk and the frequency and impact of the treatment nonadherence in this population.MPN and thromboses are linked, so it is necessary to increase our knowledge of their physiopathology to improve prevention and treatment of the events. This thesis brings some answers to some questions but, she is almost the starting point of common reflexion between clinicians and biologists interested in these domains

Axe neuro-immuno-hématopoïétique (démonstration in vitro par l'étude de l'effet d'un neuropeptide la substance P, et de son métabolite la SP 1-4, sur la pousse spontanée des progéniteurs érythroblastiques dans la polyglobulie de Vaquez)

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF