Activation of Wnt signalling in acute myeloid leukemia by induction of Frizzled-4.
Wnt signalling regulates proliferation, self renewal and cell fate. Aberrant Wnt signalling is thought to contribute to AML pathogenesis by enhancing self renewal. Herein, we provide evidence for increased expression of Frizzled-4, a receptor for Wnt ligands, in primary AML blasts compared to normal bone marrow on the protein level. In addition, Frizzled-4 is highly expressed in human CD34 positive cells as well as in lineage negative sorted mouse bone marrow cells. Functionally, Frizzled-4 expression modulates apoptosis and enhances Wnt3a induced beta-catenin stability in myeloid progenitor cells. Frizzled-4-dependent beta-catenin stabilization is dkk-1 sensitive, implicating a specific Wnt-ligand/Frizzled-receptor interaction. These findings indicate enhanced sensitivity of AML blasts for Wnt-ligands and suggest an additional mechanism of Wnt signalling activation in the pathogenesis of AML.
Tickenbrock
Lara
L
Department of Medicine, Hematology and Oncology, University of Muenster, 48149 Muenster, Germany. tickenbr@uni-muenster.de
Hehn
Sina
S
Sargin
Bülent
B
Choudhary
Chunaram
C
Bäumer
Nicole
N
Buerger
Horst
H
Schulte
Bernd
B
Müller
Oliver
O
Berdel
Wolfgang E
WE
Müller-Tidow
Carsten
C
Serve
Hubert
H
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002470:Cell Survival; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; C402930:FZD4 protein, human; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin