Immature CML cells implement a BMP autocrine loop to escape TKI treatment

International audienc

Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia.

International audienceThe mechanisms of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) often remain obscure. Analysis of patient samples during disease progression revealed the up-regulation of the oncogene TWIST-1, also measured in primary samples from TKI-resistant patients. Moreover, we found that TWIST-1 was overexpressed in CML diagnostic samples of patients who later developed cytogenetic resistance to imatinib, even those without any detectable resistance mechanism. We confirmed the up-regulation of TWIST-1 at both RNA and protein levels in imatinib-resistant cell lines, irrespective of any other resistance mechanism. Analysis with specific small interfering RNA suggested TWIST-1 involvement in the resistance phenotype. Finally, the kinetics of TWIST-1 expression during the individual medical histories of CML patients indicated that TWIST-1 expression is down-regulated by TKIs and up-regulated with TKI resistance. We hypothesize that the overexpression of the TWIST-1 oncogene represents a novel key prognostic factor potentially useful for optimizing CML management in the TKI era

Evaluation de la disponibilité des personnels qualifiés en santé maternelle et néonatale à Madagascar

A Madagascar, la situation de la santé maternelle et néonatale demeure inquiétante avec un ratio de mortalité maternelle de 478 pour 100 000 naissances vivantes et des taux de mortalité néonatale et infantile de 26 pour 1000 naissances vivantes et de 42 pour 1000 naissances vivantes, pour les enfants âgés de moins d’un mois et les enfants âgés de moins d’un an respectivement. Plusieurs facteurs pourraient expliquer cet alarmant état de santé maternelle et néonatale, y compris la pénurie de personnel de santé qualifié. Etant donné que plusieurs interventions ont été réalisées pour l’atteinte des objectifs 4 et 5 de l’OMD et qu’elles n’ont pas été fructueuses, il est pertinent d’évaluer la disponibilité des agents de santé qualifiés pour offrir les services de santé maternelle et néonatale dans les établissements sanitaires publics. L’enquête transversale a utilisé et adapté l’outil SARA (Service Availability and Readiness Assessment) de l’Organisation Mondiale de la Santé dans les 52 établissements sanitaires publics, dans 15 des 22 régions de Madagascar. Les données ont été collectées sur tablette avec le logiciel CommCare ODK© et analysées par niveau des établissements sanitaires avec le SPSS20.0. Le médecin généraliste est absent dans 14%des hôpitaux de référence et 22% des centres de santé primaire. Le nombre médian de gynécologue obstétricien dans les hôpitaux pour pratiquer les opérations césariennes est de 1. Seulement 20% des 15 régions enquêtées ont une proportion élevée (> 80%) de personnels qualifiés en santé maternelle et néonatale dans les établissements sanitaires publics. Dans l’optique d’une réduction tangible des mortalités maternelles et néonatales, l’on devrait renforcer la capacité de de ressources humaines et leur disponibilité pour offrir les services de santé maternelle et néonatale dans les établissements sanitaires publics

The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission

International audienceThe quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission

A minimal standardized human bone marrow microphysiological system to assess resident cell behavior during normal and pathological processes

International audienceBone marrow is a complex and dynamic microenvironment that provides essential cues to resident cells.We developed a standardized three-dimensional (3D) model to decipher mechanisms that control humancells during hematological and non-hematological processes. Our simple 3D-model is constituted of abiphasic calcium phosphate-based scaffold and human cell lines to ensure a high reproducibility. Weobtained a minimal well-organized bone marrow-like structure in which various cell types and secretedextracellular matrix can be observed and characterized by in situ imaging or following viable cell retrieval.The complexity of the system can be increased and customized, with each cellular component beingindependently modulated according to the issue investigated. Introduction of pathological elements inthis 3D-system accurately reproduced changes observed in patient bone marrow. Hence, we have developeda handy and flexible standardized microphysiological system that mimics human bone marrow,allowing histological analysis and functional assays on collected cells

Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature

International audienceWe report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4+ lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4+ plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4+ plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10-2 [5.7 10-4-1.79 10-1]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10-5 [2.0 10-5-6.0 10-5]), a polyclonal setting in which all IgG4+ plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10-3 at diagnosis and 1.0 10-3 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4+ plasma cell proliferation

Quelle sociologie politique pour l'enquête globale ?

Au fil d’enquêtes transnationales conduites depuis les années 1980 entre l’Amérique du Nord, l’Amérique du Sud, et l’Asie, Yves Dezalay – seul ou accompagné de son acolyte Bryant Garth – a tracé une voie originale au cœur des sciences sociales de l’international. Ancré dans la sociologie des champs et des capitaux, mais maintenant une posture toujours éclectique sur le plan théorique comme dans les pratiques d’enquête, il a ouvert la brèche d’une sociologie incarnée de la mondialisation saisie au prisme des stratégies d’internationalisation et de reproduction des élites périphériques, et des pratiques d’import-export des savoirs d’État. Aujourd’hui mobilisés dans une grande diversité́ de sous-champs d’enquêtes (sociologie des champs, économie-monde, histoire connectée, critical legal studies, relations internationales, etc.) et par plusieurs générations de chercheurs travaillant sur les objets de l’international, les travaux d’Yves Dezalay sont restés pourtant peu discutés en tant que tels. Près de trente ans après la publication de Marchands de droit (1992) qui marquait une première ouverture de la sociologie des champs aux terrains internationaux, ce numéro fait le point sur les acquis, les usages et les difficultés d’une œuvre particulièrement riche et exigeante. Il est aussi l’occasion d’un état des lieux critique sur les champs disciplinaires de l’enquête globale aujourd’hui en plein développement. Through numerous transnational investigations conducted since the 1980s between North America, South America and Asia, Yves Dezalay—alone or accompanied by his accomplice Bryant Garth—has staked out an original path within the social science of the international. Anchored in the sociology of fields and capitals while maintaining an eclectic stance both in theory and investigative practices, Dezalay has crafted an embodied sociology of globalization that problematizes the internationalization and reproduction strategies of peripheral elites alongside the import-export of state-governing expertise. Mobilized across a great diversity of scholarly sub-fields—from field theory, world-economy theory, and connected history approaches to critical legal studies and international relations—as well as by multiple generations of scholars working on international objects, the works of Yves Dezalay have never been explicitly discussed. Nearly thirty years after the publication of Marchands de droit (1992) in French, marking the first attempt to extend the sociology of fields to the international, this special issue takes stock of the achievements, uses, and difficulties of a particularly rich yet demanding research approach. Embedded in this engagement with the work of Dezalay, this issue also makes a critical inventory of the disciplinary fields wherein global approaches are developing

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Abstract In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome