Crosstalk between β-catenin and WT1 signaling activity in acute myeloid leukemia

Abstract

Crosstalk between b-catenin and WT1 signaling activity in acute myeloid leukemia Acute myeloid leukemia (AML) affects around 3,200 people annually in the UK (Cancer Research UK statistics, accessed May 2021) and is a significant health burden. New targeted therapies in AML are showing promising efficacy but further novel treatments are required which target specific molecular aberrations, reduce toxicity, and induce long-lasting remissions. One such molecular target of considerable interest given its frequent dysregulation in AML is Wnt/b-catenin signaling. b-Catenin is the central mediator of Wnt signaling and is frequently overexpressed in AML in which it is associated with poor prognosis. 1 Wnt/b-catenin is also known to drive the emergence and maintenance of leukemia stem cells in AML. 2 Protein interactions are critical to the stability, localization and activity of b-catenin, and we recently performed the first proteomic analyses of the b-catenin interactome in myeloid cells. This study identified Wilms tumor protein (WT1) as a putative novel interaction partner in myeloid cells. 3 WT1 is also overexpressed and mutated in AML, in which it confers inferior survival, 4,5 yet the interplay between these two signaling proteins has not been examined previously within a hematopoietic context. In order to idenitfy appropriate cell lines in which to study b-catenin:WT1 interplay we first performed a screen of myeloid cell lines to examine b-catenin and WT1 protein expression. We observed a statistically significant correlation between b-catenin and WT1 expression across 16 myeloid cell lines, with 50% (8/16) co-expressing b-catenin and WT1 to varying degrees (Figure There was no particular association of this correlation with cell line morphology or genotype. To validate the interaction between b-catenin and WT1 we perfomed the reciprocal WT1 co-immunoprecipitation (Co-IP) in one of the b-

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