A distinct role for the Wnt signalling protein γ-catenin in normal haematopoiesis and its dysregulation in acute myeloid leukaemia

Rhys G Morgan, Lorna Pearn, Kate Liddiard, Robert Hills, Alan Burnett, Alex Tonks, Richard Darley

Research output: Contribution to conferenceConference Paper

Abstract

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 γ catenin, a close homologue of β-catenin, as a gene dysregulated by RUNX1-ETO in normal human progenitor cells and in AML patient blasts expressing t(8;21). β catenin is known to influence both self-renewal of haematopoietic stem cells (HSC) and clinical outcome in acute myeloid leukaemia, however, little is known about the role of γ-catenin which also has structural and transcriptional roles. Here we report that γ-catenin displays a distinct subcellular localisation in normal haematopoiesis compared with β-catenin, but like β-catenin is also dysregulated in AML. Flow cytometric analysis showed that γ- and β-catenin are expressed at similar levels during normal development with both proteins being highly expressed in HSC. However, confocal microscopy showed the subcellular location of γ- and β-catenin to be distinct in HSC; γ-catenin being primarily cytoplasmic while β-catenin was predominantly nuclear-translocated (P<0.05). Expression of both catenins increased for subsequent granulocytic and monocytic differentiation, and confocal imaging revealed nuclear translocation of γ-catenin increased, whilst β-catenin expression became mainly cytoplasmic suggesting reciprocal roles for these Wnt signalling proteins in normal haematopoiesis. Overexpression of γ-catenin in a variety of leukaemic cell lines, and patient blasts, served mainly to stabilise β-catenin, which could be a mechanism promoted by RUNX1-ETO to propagate AML. Currently, we are establishing the functional role of γ-catenin in haematopoiesis by over-expression or gene silencing of γ-catenin in normal HSC
Original languageEnglish
Publication statusUnpublished - 14 Jul 2010
EventThe 17th international RUNX workshop - Hiroshima, Japan
Duration: 11 Jul 201014 Jul 2010

Workshop

WorkshopThe 17th international RUNX workshop
CountryJapan
CityHiroshima
Period11/07/1014/07/10

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    Morgan, R. G., Pearn, L., Liddiard, K., Hills, R., Burnett, A., Tonks, A., & Darley, R. (2010). A distinct role for the Wnt signalling protein γ-catenin in normal haematopoiesis and its dysregulation in acute myeloid leukaemia. Paper presented at The 17th international RUNX workshop, Hiroshima, Japan.