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Etudes des altérations fonctionnelles de la signalisation dépendante du récepteur à l’antigène dans les cellules B de la Leucémie Lymphoïde Chronique

Abstract : Altered B-cell antigen receptor (BCR) signaling pathways play a key role in chronic lymphocytic leukemia(CLL) pathophysiology. Our lab has previously shown that ex-vivo antigenic stimulation of CLL-B cells led todifferential cell survival and cell migration, which allowed the distinction between two groups of patients. Basedon these results, we evidenced that the cell survival advantage in response to BCR engagement from one groupdepends on 1) a critical threshold mediated by the early effector expression levels (BCR, Syk et Zap70), a BCR competency of the leukemic cells translated by Syk phosphorylation, PLCƳ2 activation, intracellular Ca2+mobilization and the transcription factor NFAT2 activation; this activated BCR/NFAT signaling cascade, which is reflected by the ex-vivo measurement of CLL cell survival, was correlated to the overall survival from CLLpatients; 2) increased levels of global and specific Syk phosphorylation, phospho-Syk subcellular distribution, Sykability to interact with positive and negative effectors and to activate them. Moreover, study of BCR stimulation mediated decreased migration in CLL B cells showed that it relied on CXCR4 internalization levels that were regulated by activated PI3Ks acting upstream of the PKDs; activation of the latters allowed CXCR4 phosphorylation and then its endocytosis. Altogether, these data allowed us to better understand the molecular mechanisms underlying the survival advantage and the decreased migration of CLL B cells in response to antigenic stimulation, to evidence eventual functional biomarkers of stratification (pSyk and pPLCƳ2), to point out potential therapeutic targets (NFATs and PKDs), and to partially explain how Fostamatinib and Idelalisib function as therapeutic drugs in CLL.
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Submitted on : Wednesday, December 13, 2017 - 10:53:30 AM
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Maude Quettier. Etudes des altérations fonctionnelles de la signalisation dépendante du récepteur à l’antigène dans les cellules B de la Leucémie Lymphoïde Chronique. Biologie moléculaire. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCD055⟩. ⟨tel-01662468⟩

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