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
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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