A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia.
Relapses following chemotherapy are a major hindrance to patients' survival in acute myeloid leukemia (AML). To investigate the role of the hematopoietic niche in the chemoresistance of leukemic cells, we examined two pathways: one mediated by adhesion molecules/integrins, and the other by soluble factors of the morphogen Wnt pathway. In our study, both the adhesion of leukemic blasts to fibronectin and the addition of Wnt antagonists induced, independently, resistance of AML cells to daunorubicin in a cell survival assay. Using pharmacological inhibitors and siRNA, we showed that both resistance pathways required the activity of the glycogen synthase kinase 3beta (GSK3beta). Moreover, the AML cell protection downstream of GSK3beta was mediated by NF-kappaB. A link between the adhesion and the Wnt pathway was found, as adhesion of U937 on human osteoblasts, a component of the hematopoietic niche, triggered the secretion of the Wnt antagonist sFRP-1 and supported resistance to daunorubicin. The osteoblast-conditioned medium could also confer chemoresistance to U937 cells cultured in suspension, and this cell protective effect was abrogated after depletion of sFRP-1. In the context of this potential double in vivo resistance, modulators of the common signal GSK3beta and of its target NF-kappaB could represent important novel therapeutic tools.
De Toni
F
F
Département d'Oncogenèse et Signalisation Cellulaire dans les Cellules Hématopoïétiques, Institut National de la Santé et de la Recherche Médicale Unité 563, Centre Hospitalier Universitaire Purpan, Toulouse, France.
Racaud-Sultan
C
C
Chicanne
G
G
Mas
V Mansat-De
VM
Cariven
C
C
Mesange
F
F
Salles
J-P
JP
Demur
C
C
Allouche
M
M
Payrastre
B
B
Manenti
S
S
Ysebaert
L
L
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001752:Blast Crisis; D002448:Cell Adhesion / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D020298:U937 Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
D000903:Antibiotics, Antineoplastic; D017077:Culture Media, Conditioned; D003630:Daunorubicin; D005353:Fibronectins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051153:Wnt Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C000605506:GSK3B protein, human