title: Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors.
abstract: 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.
authors: Inserm U1043, CNRS U5282, Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse UPS, Toulouse, France.
authors: J
authors: J
authors: Bertrand
authors: M
authors: M
authors: Despeaux
authors: S
authors: S
authors: Joly
authors: E
authors: E
authors: Bourogaa
authors: N
authors: N
authors: Gallay
authors: C
authors: C
authors: Demur
authors: P
authors: P
authors: Bonnevialle
authors: F
authors: F
authors: Louache
authors: V
authors: V
authors: Maguer-Satta
authors: N
authors: N
authors: Vergnolle
authors: B
authors: B
authors: Payrastre
authors: C
authors: C
authors: Racaud-Sultan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034622:RNA Interference; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D053650:Interleukin-3 Receptor alpha Subunit; D008301:Maleimides; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C417521:SB 216763; D005047:Etoposide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D019204:GTP-Binding Proteins