Targeting b-catenin in acute myeloid leukaemia

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Abstract

Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of the bone marrow with a poor prognosis. Current chemotherapies show limited efficacy and so novel therapies are required that target specific molecular aberrations. One such candidate is β-catenin, the central mediator of Wnt signalling, which is frequently overexpressed, mislocalised and overactive in AML where it sustains leukaemia stem cells (LSC). The stability, localisation and activity of b-catenin is dictated heavily by protein interactions which were previously poorly characterised in a haematopoietic context.

We recently performed the first β-catenin interactome analysis in myeloid leukaemia cells and revealed a plethora of novel interactions for b-catenin including the significant enrichment of RNA binding proteins (RBPs). The RBPs were associated with GO search terms ‘mRNA processing and transport’ and ‘rRNA processing and transport’ and validated b-catenin:RBP interactions to date include LIN28B, WT1 and MSI2. b-Catenin has well established roles in transcription however this data, coupled with previous reports of β-catenin binding mRNA and regulating alternative splicing, raises the intriguing possibility that b-catenin could also have a role in post-transcriptional gene control in AML. To identify transcripts with which b-catenin is associated we have performed RBP-immunoprecipitation (RIP) for b-catenin coupled to RNA sequencing (RIPseq) in AML cells. These analyses have identified and validated b-catenin association with several RNA targets involved in critical cellular processes including myeloid differentiation (CSF1, CEBPA, PML), autophagy (RPTOR, DAPK3, WDR6) and most abundantly the Wnt signalling pathway itself (AMER1, APC, BCL9L, LEF1, TCF7, AXIN2, RNF43).

The existence of positive and negative feedback loops within Wnt signalling has been known for some time and are thought to be driven exclusively through TCF/LEF mediated transcriptional mechanisms since many are confirmed Wnt target genes. However, our new data raise the tantalising prospect that b-catenin may also govern Wnt signalling feedback loops post-transcriptionally, especially since many are not established transcriptional Wnt target genes (e.g., AMER1, APC, BCL9L).

We are now investigating the functional impact of b-catenin on these bound RNAs, and the wider consequence of these interactions for the development of both normal haematopoietic stem cells (HSC) and AML LSC.