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Nantes, France

Le Coz M.,Institute Curie | Le Coz M.,French National Center for Scientific Research | Le Coz M.,French Institute of Health and Medical Research | Le Coz M.,Equipe Labellisee | And 6 more authors.
Experimental Dermatology | Year: 2014

We show, for the first time, that melanocytes can form a primary cilium in vitro, corresponding to an immotile or sensory cilium. Such cilia are observed when melanocytes reach confluence or when medium nutrient levels are insufficient. This observation should greatly improve our understanding of the signal transduction processes potentially occurring in these cells during embryonic development, homeostasis in adulthood and melanomagenesis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source


El Hajj H.,American University of Beirut | El-Sabban M.,American University of Beirut | Hasegawa H.,Japan National Institute of Infectious Diseases | Hasegawa H.,University College Dublin | And 12 more authors.
Journal of Experimental Medicine | Year: 2010

Chronic HTLV-I (human T cell lymphotropic virus type I) infection may cause adult T cell leukemia/lymphoma (ATL), a disease with dismal long-term prognosis. The HTLV-I transactivator, Tax, initiates ATL in transgenic mice. In this study, we demonstrate that an As2O3 and IFN-α combination, known to trigger Tax proteolysis, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy abrogated initial leukemia engraftment into secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasome function. A similar regimen recently yielded unprecedented disease control in human ATL. Our demonstration that this drug combination targeting Tax stability abrogates tumor cell immortality but not short-term growth may foretell a favorable long-term efficiency of this regimen in patients. © 2010 El Hajj et al. Source


Damm F.,French Institute of Health and Medical Research | Damm F.,Institute Gustave Roussy | Mylonas E.,French Institute of Health and Medical Research | Mylonas E.,Institute Gustave Roussy | And 56 more authors.
Cancer Discovery | Year: 2014

Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. © 2014 American Association for Cancer Research. Source


Shirinian M.,American University of Beirut | Kambris Z.,American University of Beirut | Hamadeh L.,American University of Beirut | Grabbe C.,Umea University | And 11 more authors.
Journal of Virology | Year: 2015

Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this new in vivo model. © 2015, American Society for Microbiology. Source


Jacque N.,French Institute of Health and Medical Research | Jacque N.,Equipe Labellisee | Ronchetti A.M.,French Institute of Health and Medical Research | Ronchetti A.M.,Equipe Labellisee | And 44 more authors.
Blood | Year: 2015

Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34+ progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GACK320A allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML. © 2015 by The American Society of Hematology. Source

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