Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia

Simon M, Grandage VL, Linch DC and Khwaja A
Source: Oncogene
Publication Date: (2005)
Issue: 24(14): 2410-2420
Research Area:
Immunotherapy / Hematology
Cells used in publication:
CD34+ cell, human
Species: human
Tissue Origin: blood
Species: human
Tissue Origin: blood
Nucleofectorâ„¢ I/II/2b
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.Oncogene advance online publication, 14 February 2005; doi:10.1038/sj.onc.1208431