Activation of Wnt/beta-catenin pathway mediates growth and survival in B-cell progenitor acute lymphoblastic leukaemia.
This study investigated the response of acute lymphoblastic leukaemia (ALL) cells to Wnt proteins. Accumulation of beta-catenin was measured by Western blotting and immunofluorescence microscopy. Reverse transcription polymerase chain reaction (RT-PCR) analysis of B-cell progenitor acute lymphoblastic leukaemia (ALL) cells revealed expression of Wnt genes, including WNT2B in 33%, WNT5A in 42%, WNT10B in 58% and WNT16B in 25% of cases. The Wnt receptors, (Frizzled) FZD7 and FZD8 were also expressed in most cases while FZD3, FZD4 and FZD9 were occasionally detected. Stimulation of ALL cells with Wnt-3a activated canonical Wnt signalling with increased expression and nuclear translocation of beta-catenin. This resulted in a 1.7- to 5.3-fold increase in cell proliferation, which was associated with enhanced cell cycle entry. A significant increase in the survival of ALL cells under conditions of serum deprivation was also observed. Microarray analysis and quantitative RT-PCR revealed that activation of the Wnt/beta-catenin pathway led to altered expression of genes involved in cell cycle regulation and apoptosis in normal and leukaemic B-cell progenitors. Our results demonstrate that Wnt-3a provides proliferative and survival cues in ALL cells. This data suggests that targeting the Wnt signalling pathway may be a useful therapeutic strategy in ALL.
Khan
Naveed I
NI
Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, SW, Australia.
Bradstock
Kenneth F
KF
Bendall
Linda J
LJ
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western / Q000379:methods; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism*
D018797:Cell Cycle Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin