Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.: CYCLON-induced Rituximab resistance

International audienceImmuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma

A transcriptomic analysis of human centromeric and pericentric sequences in normal and tumor cells

Although there is now evidence that the expression of centromeric (CT) and pericentric (PCT) sequences are key players in major genomic functions, their transcriptional status in human cells is still poorly known. The main reason for this lack of data is the complexity and high level of polymorphism of these repeated sequences, which hampers straightforward analyses by available transcriptomic approaches. Here a transcriptomic macro-array dedicated to the analysis of CT and PCT expression is developed and validated in heat-shocked (HS) HeLa cells. For the first time, the expression status of CT and PCT sequences is analyzed in a series of normal and cancer human cells and tissues demonstrating that they are repressed in all normal tissues except in the testis, where PCT transcripts are found. Moreover, PCT sequences are specifically expressed in HS cells in a Heat-Shock Factor 1 (HSF1)-dependent fashion, and we show here that another independent pathway, involving DNA hypo-methylation, can also trigger their expression. Interestingly, CT and PCT were found illegitimately expressed in somatic cancer samples, whereas PCT were repressed in testis cancer, suggesting that the expression of CT and PCT sequences may represent a good indicator of epigenetic deregulations occurring in response to environmental changes or in cell transformation

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of <i>TP53</i> mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Rôle pathologique des anomalies de l'hétérochromatine péricentromérique du chromosome 1 dans les lymphomes B malins non-Hodgkiniens

Les réarrangements chromosomiques affectant la région d'hétérochromatine constitutive du chromosome 1 humain (bande cytogénétique 1q12) sont remarquablement fréquents dans les lymphomes, les myélomes, les leucémies aiguês et dans certaines tumeurs solides. Ceci suggère fortement l'existence de mécanismes oncogéniques dépendant de l'hétérochromatine constitutive dans ces maladies. Mes travaux de thèse montrent que ces réarrangements induisent des altérations profondes de l'organisation et de la fonction de la chromatine dans des cellules de lymphome B. Les conséquences majeures sont la formation de foyers hétérochromatiques aberrants résultant d'appariements intra-chromosomiques 'longue distance' entre le domaine d'hétérochromatine 1q12 réarrangé et le domaine centromérique. Ces foyers sont associés à un enrichissement de l'euchromatine adjacente en marques épigénétiques répressives, et à la répression de l'expression de gènes, parmi lesquels GMCL 1 et MXD1 qui codent pour des protéines impliquées dans le contrôle de la signalisation P53 et MYC, respectivement. D'autre part, l'étude pilote de profiling transcriptionnel par puces Affymetrix dans des cas de lymphome avec ou sans anomalie de l'hétérochromatine 1q12 confirme et identifie de nouvelles cibles de dérégulation liées à l'hétérochromatine dans les lymphomes B non-Hodgkiniens. La compréhension du rôle de ces foyers hétérochromatiques aberrants présenterait un intérêt majeur pour les tumeurs hématologiques ou solides, puisque ces anomalies sont observées de manière fréquente et non-aléatoire dans un large spectre de tumeurs humaines, et sont associées à la progression tumorale et à un mauvais pronostic.Chromosomal rearrangements targeting human chromosome 1 constitutive heterochromatin region (cytogenetic band 1q12) are remarkably frequent in Iymphoma, myeloma, acute leukaemia and in some solid tumours. This highly suggests existence of constitutive heterochromatin-dependent oncogenic mechanisms in these diseases. My PhD works show that these rearrangements induce profound alterations of chromatin organisation and function in Iymphoma B-cells. Major consequences are the formation of aberrant heterochromatic foci resulting from long range intra-chromosomal 'matching' between the rearranged 1q12 and centromeric regions. These foci are associated with an enrictfment of adjacent euchromatic sequences in repressive epigenetic marks, and with deregulated expression of genes such as GMCL 1 and MXD1 which encodes proteins involved in the control of P53 and MYC pathways, respectively. ln the other hand, a pilot study of transcriptional profiling by Affymetrix arrays in cases of human Iymphoma with or without 1 q12 heterochromatin rearrangement confirms and identifies new targets for deregulation linked to heterochromatin in non-Hodgkin B-ceillymphoma. Understanding the role of these aberrant heterochromatic foci would be of major interest for haematological and solid tumours, since these anomalies are frequent and non-random in a large panel of human tumours, and are associated to tumour progression and poor prognosis.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Etude de la physiopathologie du récepteur FcgRIIB dans les lymphomes B malins non-Hodgkiniens

Le récepteur de basse affinité pour les fragments Fc des immunoglobulines G, FcgammaRIIB, joue un rôle clé dans la régulation négative des réponses immunes. Il est capable d'inhiber les fonctions cellulaires B induites par le BCR, ainsi que à induire un processus de mort cellulaire, encore très peu caractérisée dans la littérature. Récemment, un rôle potentiel de FcgammaRIIB dans la tumorigenèse a été identifié. En particulier, la dérégulation de l'expression de FcgammaRIIB suite à des translocations chromosomiques a été rapportée dans des cas de lymphomes folliculaires. Nous avons, ainsi étudié les conse quences du recrutement des récepteurs FcgammaRIIB dans des lignées de lymphome B. Nous montrons que le co-recrutement de récepteurs FcgammaRII à l'aide d'anticorps anti-FcgammaRII (FLI 8.26) induit la mort cellulaire de cellules de lymphome B, mais n'induit pas la mort des lymphocytes B normaux. Ce processus apoptotique dans les cellules tumorales B est caspase dépendant (libération du cytochrome c, clivage de la caspase-9, activation de la caspase-3) et indépendant (libération d'AIF). Nous montrons que la phosphorylation des récepteurs FcgammaRIIB est un événement précoce dans la voie de signalisation apoptotique. De plus, le traitement par FLI 8.26 a induit l'expression de la protéine HSP27. Nos résultats ont montré pour la première fois les mécanismes de mort cellulaire FcgammaRIIB dépendante dans les lymphomes B humains. Nous suggérons que la mort cellulaire FcgammaRIIB dépendante pourrait ainsi, être mise à profit en thérapeutique.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Cognitive impairment in multiple sclerosis: clinical and nuclear magnetic resonance imaging correlates

Fifty-eight patients with Clinically Definite Multiple Sclerosis (MS) and forty-eight patients with clinically isolated lesions (CIL) of the kind frequently observed in MS, were psychometrically examined with a range of neuropsychological tests. The results were examined in conjunction with Magnetic Resonance Imaging (MRI), neurological, psychiatric and physical ability evidence and compared to a matched group of forty-six controls. A method is described for calculating the overall cognitive efficiency of each individual and this measure is examined in relation to MRI, neurological, psychiatric and motor ability evidence. Measures of the cognitive speed of memory and object-naming are examined and the relationship between accuracy and speed on these functions is explored. The MS group present with intact accuracy on Verbal Recognition Memory and Object-naming while demonstrating slowed cognitive processing in both functions. The CIL group also present with intact accuracy on these functions and, in addition. Abstracting Ability and accuracy of Visual Recognition Memory are intact: however, CIL patients demonstrate slowed cognitive processing on Visual Recognition Memory, as do the MS group. Dissociation between speed and accuracy was observed for MS and CIL patients and this is discussed with regard to the concept of 'subcortical' dementia. The interaction of speed with accuracy is different between the three groups with the CIL group occupying the intermediate level. Impairment of function within the MS group is demonstrated to be related to lesions observed on MRI. Cognitive impairment within the CIL group, however, was not established as a correlate of MRI lesions but would seem to relate to disease status. The results of the present study present evidence of impairment of cognitive efficiency and cognitive speed in patients with MS and in CIL patients. The level of impairment of the CIL group is intermediate when compared to that of the MS group and the controls

Caractérisation épigénétique du lymphome du manteau

Les lymphomes du manteau (MCL) sont des lymphomes B à petites cellules, rares et particuliers de par leur pronostic sombre et leur évolution rapide (médiane de survie de 3-4 ans). Les objectifs clés autour de cette maladie sont : l identification de marqueurs moléculaires prédictifs de l évolution et le développement de thérapies innovantes. De nombreuses études ont étayé le rôle prépondérant d anomalies épigénétiques dans l initiation et la progression des cancers. L intérêt de ce projet est d établir le profil épigénétique du lymphome du manteau, d identifier les localisations des anomalies observées et d étudier les gènes modificateurs de la méthylation des histones. De façon tout à fait remarquable, les observations faites en immunohistochimie sur ganglions lymphatiques réactionnels pointent le rôle important de la dynamique du remodelage de la chromatine, en particulier pour H4K20me3, au cours de la prolifération / différentiation lymphoïde B antigène-dépendante. Nous avons identifié des cas de MCL pour lesquels le patron observé dans les hyperplasies ganglionnaires est largement perturbé. En effet, sur une série de 19 patients, il coexiste deux profils distincts pour la marque d hétérochromatine constitutive H4K20me3, des cas négatifs et des cas fortement positifs. L hypothèse d une dérégulation de l expression des enzymes mettant en place ou effaçant ces marques ne semble pas évidente. Les altérations de l hétérochromatine constitutive apparaissent désormais comme une perturbation épigénétique récurrente dans le MCL. Ces profils épigénétiques pourraient permettre de dégager des marqueurs pronostiques pertinents et de développer de nouvelles stratégies thérapeutiques ciblées.Mantle Cell Lymphomas (MCLs) are rare small cell lymphomas B, characterized by a dark prognosis and a fast evolution (median of survival: 3-4 years). There is thus a strong need to identify predictive molecular markers of the evolution and to develop innovative therapies in this disease. Numerous studies support the important role of epigenetics abnormalities in the initiation and the progression of cancers. This project aimed to establish the epigenetic profile of MCL, to identify the localizations of the observed abnormalities and to study the genes regulating histone methylation. Remarkably, the observations made by immunohistochemistry on reactive lymph nodes pointed towards the important role of the dynamics of the reshaping of chromatin, in particular for H4K20me3, during the antigen dependent B cell proliferation / differentiation process . We identified cases of MCL for which the profile observed in the reactive lymph nodes was widely perturbed. Indeed, in a series of 19 patients, two different profiles for the H4K20me3 heterochromatin mark coexisted; negative cases and strongly positive cases. The hypothesis of a deregulation of the expression of the enzymes setting up or erasing these marks does not seem evident. The changes in constitutive heterochromatin appear henceforth as epigenetic recurring disturbance in MCL. The epigenetics profiles could allow the identification of relevant prognosis markers and the development of new targeted therapeutic strategies.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF