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International audience; Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease.

Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K–AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance. Significance: We have discovered the first relapse-specific BTK mutation in patients with MCL with acquired resistance, but not primary resistance, to ibrutinib, and demonstrated a rationale for targeting the proliferative resistant MCL cells by inhibiting CDK4 and the cell cycle in combination with ibrutinib in the presence of BTKWT or a PI3K inhibitor independent of BTK mutation. As drug resistance remains a major challenge and CDK4 and PI3K are dysregulated at a high frequency in human cancers, targeting CDK4 in genome-based combination therapy represents a novel approach to lymphoma and cancer therapy. Cancer Discov; 4(9); 1022–35. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973

In this work, we are interested in the evolution of water waves under the influence of a non constant atmospheric pressure, a moving bottom and a Coriolis forcing. In a first part, we study the Proudman resonance. We propose a mathematical approach to understand this phenomenon. First, we prove a local wellposedness result in a irrotational framework on the water waves equations (also called the Zakharov/Craig-Sulem formulation). Then, we fully justify different asymptotic models. In particular, we carefully study the Proudman resonance in deep water in the linear regime. Finally, we study the propagation of water waves in a weakly nonlinear regime thanks to the Saut-Xu equations and we propose a numerical scheme in order to solve these equations. In a second part, we study the influence of a Coriolis forcing on water waves. We prove a local wellposedness result on the Castro-Lannes equations, which generalize the Zakharov/Craig-Sulem formulation in the rotational framework. Then, we fully justify different asymptotic models when we take into account a Coriolis forcing. In particular, we generalize the Boussinesq equations (asymptotic model in a weakly nonlinear regime) in this setting. Thanks to these equations, we justify the Poincaré waves and then the Ostrovsky equation, which generalize the Korteweg-De- Vries equation when a Coriolis forcing is taking into account.; Dans ce travail nous nous intéressons aux comportement de vagues soumises à l’action d’une pression atmosphérique non constante, un fond mobile et la force de Coriolis. Une première partie est dédiée à l’étude de la résonance de Proudman. Nous proposons une approche mathématique rigoureuse pour étudier ce phénomène. Nous commençons par démontrer un résultat d’existence locale dans un cadre irrotationnel sur les équations des vagues (appelées aussi formulation de Zakharov/Craig-Sulem). Puis, nous justifions différents modèles asymptotiques pour généraliser cette résonance dans diverses situations physiques. Nous proposons en particulier une étude détaillée dans des eaux profondes dans un régime linéaire. Nous étudions aussi la propagation de vagues dans des eaux profondes dans un régime faiblement non-linéaire grâce aux équations de Saut-Xu et nous proposons un schéma numérique pour résoudre ces équations. Dans une deuxième partie, nous étudions l’effet de la force de Coriolis sur les vagues. Nous démontrons un résultat d’existence locale sur les équations Castro-Lannes, équations qui généralisent la formulation de Zakharov/Craig-Sulem dans un cadre rotationnel. Nous justifions ensuite différents modèles asymptotiques dans des eaux peu profondes en présence de la force de Coriolis. En particulier, nous proposons une généralisation des équations de Boussinesq (modèle asymptotique dans un régime faiblement linéaire) lorsque la force de Coriolis n’est pas négligeable. Ces équations nous permettent ensuite de justifier mathématiquement les ondes de Poincaré puis l’équation d’Ostrovsky qui généralise l’équation de Korteweg-De-Vries en présence de la force de Coriolis.

Abstract 127 The purpose of this study was to identify the pathways associated with the ability of human myeloma cells (HMCLs) to spontaneous self-renew in a serum-free semi-solid human collagen-based assay. Among 32 HMCLs analyzed, 8 were able to grow spontaneously (from 5% to 35% of seeded cells) without any addition of cytokines or growth factors and this capacity to grow correlated with the presence of RAS mutations (p=0.04). Gene expression profile analysis of HMCLs identified one gene, JAG2, overexpressed in HMCLs that are able to self-renew. Interestingly, flow cytometry analysis of JAG2 expression showed that the level of membrane JAG2 expression positively correlated (r=0.87) to the percentage of colony formation (p=0.004). Blocking Jag-Notch interactions with Notch-Fc chimeric molecules impaired self-colony formation underlying a role for Jag-Notch pathway in colony formation. Furthermore, direct JAG2 silencing in two independent HMCLs (KMM1 and JJN3) prevented colony formation. Moreover, xenografts in SCID mice showed that JAG2 silencing fully impaired tumor growth of both KMM1 and JJN3. RT-PCR evaluation of JAG2 expression showed that 20 of 30 CD138+ purified primary myeloma cells expressed JAG2 and a Jag2+ subpopulation was identified by flow cytometry within primary CD138+ MM cells of patients at diagnosis or relapse. We further identified the growth factors involved in the self-renewal. By using blocking anti-IGF1R Ab or C-KIT inhibitor (imatinib mesylate), we showed that self-renewal of HMCLs was dependent on IGF1/IGF1R (5 of 8) or on C-KIT/SCF (1) or on both loops (2 of 8). Of note, C-KIT+ HMCLs expressed high JAG2 level at the cell membrane that was decreased by imatinib mesylate. Interestingly, none HMCL self-renewal was dependent on IL6/IL6R loop despite the high efficiency of paracrine IL6 to induce colony formation in most HMCLs. To address expression of C-KIT/SCF and IGF1R/IGF1 in primary myeloma cells, we used public data from patients at diagnosis published by Arkansas University. Expression of C-KIT and IGF1R was found in 56% and 50% of patients at diagnosis, respectively: 53% of patients express one or the other receptor, 27% express both and 20% express none. Expression of receptors is not similar with regard to the molecular classification of patients as previously shown by cytometry: indeed, MS patients underexpress C-KIT (p Disclosures: No relevant conflicts of interest to declare.