A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
Autor: | Véronique Maguer-Satta, Mauricette Michallet, Fawzia Louache, Marion Billandon, Frédéric Mazurier, Franck-Emmanuel Nicolini, Ali Nehme, Claude Caron de Fromentel, Amine Belhabri, Mario Flores-Violante, Xavier Thomas, Etienne Paubelle, Thibault Voeltzel, Sandrine Jeanpierre, Stéphane Joly, Milen Milenkov, Sylvain Lefort, Florence Zylbersztejn, Gaelle Fossard |
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Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire des pathogènes émergents -- Emerging Pathogens Laboratory (LPE-Fondation Mérieux), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ERL 7001, CNRS, Tours, France, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Homeobox protein NANOG Cancer Research Myeloid [SDV]Life Sciences [q-bio] Immunology [SDV.CAN]Life Sciences [q-bio]/Cancer Bone Morphogenetic Protein 4 Biology Bone morphogenetic protein Article 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor medicine Tumor Microenvironment Humans Bone morphogenetic protein receptor [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology lcsh:QH573-671 ComputingMilieux_MISCELLANEOUS Bone Morphogenetic Protein Receptors Type I lcsh:Cytology Myeloid leukemia [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Cell Biology Nanog Homeobox Protein medicine.disease 3. Good health Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure embryonic structures Cancer research Neoplastic Stem Cells Bone marrow Stem cell [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Signal Transduction |
Zdroj: | Cell Death & Disease Cell Death and Disease Cell Death and Disease, 2018, 9 (10), ⟨10.1038/s41419-018-1042-7⟩ Cell Death and Disease, Nature Publishing Group, 2018, 9 (10), ⟨10.1038/s41419-018-1042-7⟩ Cell Death and Disease, Vol 9, Iss 10, Pp 1-12 (2018) |
ISSN: | 2041-4889 |
Popis: | 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. |
Databáze: | OpenAIRE |
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