Acute myeloid leukaemia (AML) is a heterogenous clonal disorder of haematopoietic cells. A common abnormality in AML (~12%) is the t(8;21)(q22;q22) RUNX1-ETO fusion. Previously we identified the genes dysregulated by RUNX1-ETO in normal human progenitor cells and AML patient blasts expressing t(8;21). This analysis identified significant overexpression of γ catenin which is a member of the armadillo protein family and a close homologue of β catenin. Like ß catenin, it acts as a transcription factor and also functions in cell membrane-associated structures. Despite the known significance of Wnt signalling in haematopoiesis and AML little is known concerning the role of γ-catenin in these contexts. Here we report the significance of γ-catenin expression in normal haematopoeisis and in AML patient samples. Since the t(8;21) is associated with good clinical outcome we determined the correlation of γ-catenin expression with survival in a cohort of 170 AML patients. There was evidence that higher expression was associated with lower remission rates (OR 1.27 per log increase, P=0.05) arising from resistant disease (OR 1.71, P=0.02). To understand the potential basis of a pathological role of γ-catenin in AML, we analysed γ catenin expression in haematopoietic developmental subsets. γ-Catenin was highly expressed in haematopoietic stem and progenitor cells with expression being maintained throughout subsequent myeloid development whilst it was downregulated in lymphoid cells and absent through erythroid maturation. To decipher the functional role of γ-catenin in haematopoiesis, its subcellular location was analysed using confocal microscopy. Normal progenitor cells demonstrated predominantly nuclear excluded γ-catenin whereas AML blasts from patients with poor clinical outcome exhibited significant (P<0.05) nuclear translocation of γ-catenin. We are currently examining the intracellular distribution of γ-catenin in other AML samples including t(8;21) patients. Taken together this data suggests that RUNX1-ETO may alter transcriptional dysregulation in AML through promoting γ-catenin nuclear signaling.
|Publication status||Unpublished - 19 Aug 2009|
|Event||RUNX Transcription Factors in Development & Disease - Oxford, United Kingdom|
Duration: 16 Aug 2009 → 19 Aug 2009
|Workshop||RUNX Transcription Factors in Development & Disease|
|Period||16/08/09 → 19/08/09|