Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia.
The beta-catenin protein is at the core of the canonical Wnt signalling pathway. Wnt stimulation leads to beta-catenin accumulation, nuclear translocation and interaction with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to regulate genes important for embryonic development and proliferation. Wnt/beta-catenin can promote stem cell self-renewal and is dysregulated in colon carcinoma. We have examined the role of the Wnt pathway in the development of acute myeloid leukaemia (AML) and find that the beta-catenin protein is readily detected in primary AML samples. Using transfection of a TCF/LEF reporter construct into primary AML cells and normal human progenitors, we find increased reporter activity in 16/25 leukaemia samples. Retrovirally mediated expression of a mutant active beta-catenin in normal progenitors preserves CD34 expression and impairs myelomonocytic differentiation. Activation of TCF/LEF signalling decreases factor withdrawal-induced apoptosis of normal progenitors. A significant proportion of AML cases show aberrant expression of components of the Wnt pathway including Wnt-1, Wnt-2b and LEF-1. These results provide evidence for the involvement of the Wnt/beta-catenin pathway in the pathogenesis of AML.
Simon
Maria
M
Department of Haematology, Royal Free & University College Medical School, 98 Chenies Mews, London WC1E 6HX, UK.
Grandage
Victoria L
VL
Linch
David C
DC
Khwaja
Asim
A
D000208:Acute Disease; D001483:Base Sequence; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin