Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors
| Autor: | Jessica Bertrand, Bernard Payrastre, N Gallay, Nathalie Vergnolle, Véronique Maguer-Satta, Mathieu Despeaux, Cécile Demur, Ezzeddine Bourogaa, S Joly, P Bonnevialle, F Louache, Claire Racaud-Sultan |
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| Přispěvatelé: | ANDRA, Laboratoire d'Hématologie [Purpan], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Equipe 11, Centre de Recherche en Cancérologie de Lyon ( 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 ) -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 ), Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [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), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud |
| Rok vydání: | 2011 |
| Předmět: |
Male
MESH : Aged Antigens CD34 MESH : Blotting Western [ SDV.CAN ] Life Sciences [q-bio]/Cancer Glycogen Synthase Kinase 3 0302 clinical medicine MESH : Indoles MESH : Tumor Cells Cultured GSK-3 Tumor Cells Cultured Protein Phosphatase 2 MESH : GTP-Binding Proteins Cells Cultured MESH: Glycogen Synthase Kinase 3 MESH: Etoposide Etoposide MESH: Indoles MESH : Maleimides Aged 80 and over MESH : Cell Survival 0303 health sciences education.field_of_study MESH: Middle Aged MESH: Protein Phosphatase 2 Neoplasm Proteins MESH: Cell Survival MESH: Young Adult 030220 oncology & carcinogenesis Neoplastic Stem Cells RNA Interference MESH: Cells Cultured MESH : Protein Phosphatase 2 MESH : Glycogen Synthase Kinase 3 MESH: Antineoplastic Agents Phytogenic Blotting Western MESH : Young Adult Receptors Cell Surface MESH: Cell Adhesion 03 medical and health sciences MESH : Neoplasm Proteins MESH: Sex Factors Genetics MESH: Blotting Western Humans MESH : Middle Aged MESH: Tumor Cells Cultured Progenitor cell MESH : Aged 80 and over Clonogenic assay education Molecular Biology Aged MESH: Interleukin-3 Receptor alpha Subunit MESH: Humans Glycogen Synthase Kinase 3 beta MESH : Hematopoietic Stem Cells MESH : Humans MESH : Leukemia MESH: Adult MESH: Antigens CD34 Protein phosphatase 2 Hematopoietic Stem Cells MESH: Neoplastic Stem Cells Immunology MESH: Female MESH: Neoplasm Proteins Cancer Research Indoles MESH : Receptors Cell Surface MESH : Interleukin-3 Receptor alpha Subunit MESH : Antineoplastic Agents Phytogenic MESH: Hematopoietic Stem Cells Maleimides MESH: Aged 80 and over MESH : Female MESH: Maleimides MESH: Receptors Cell Surface MESH: Aged Leukemia Myeloid leukemia MESH : Adult Middle Aged medicine.anatomical_structure MESH : Antigens CD34 Female Stem cell Adult MESH: GTP-Binding Proteins Cell Survival MESH : Male MESH : Sex Factors MESH: RNA Interference Population Interleukin-3 Receptor alpha Subunit [SDV.CAN]Life Sciences [q-bio]/Cancer MESH : Etoposide Biology Receptors for Activated C Kinase Young Adult MESH : Neoplastic Stem Cells Sex Factors GTP-Binding Proteins MESH: Leukemia MESH : Cells Cultured Cell Adhesion medicine 030304 developmental biology Antineoplastic Agents Phytogenic MESH: Male MESH : Cell Adhesion Cancer research Bone marrow MESH : RNA Interference |
| Zdroj: | Oncogene Oncogene, Nature Publishing Group, 2012, 31 (6), pp.694-705. 〈10.1038/onc.2011.258〉 Oncogene, Nature Publishing Group, 2012, 31 (6), pp.694-705. ⟨10.1038/onc.2011.258⟩ |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.258 |
| Popis: | International audience; Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3β (GSK3β) by serine 9-dephosphorylation. Strikingly, GSK3β-mediated survival was restricted to leukemic progenitors from female patients. GSK3β inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of α(5)β(1)-integrin engagement, was specifically upregulated and controlled GSK3β activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3β-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3β as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy. |
| Databáze: | OpenAIRE |
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