Targeting β-catenin in acute myeloid leukaemia: past, present, and future perspectives

Abstract

Acute myeloid leukaemia (AML) is an aggressive disease of the bone marrow with a poor prognosis. Evidence suggests long established chemotherapeutic regimens used to treat AML are reaching the limits of their efficacy, necessitating the urgent development of novel targeted therapies. Canonical Wnt signalling is an evolutionary conserved cascade heavily implicated in normal developmental and disease processes in humans. For over 15 years its been known that the central mediator of this pathway, β-catenin, is dysregulated in AML promoting the emergence, maintenance, and drug resistance of leukaemia stem cells. Yet, despite this knowledge, and subsequent studies demonstrating the therapeutic potential of targeting Wnt activity in haematological cancers, β-catenin inhibitors have not yet reached the clinic. The aim of this review is to summarise the current understanding regarding the role and mechanistic dysregulation of β-catenin in AML, and assess the therapeutic merit of pharmacologically targeting this molecule, drawing on lessons from other disease contexts.

Keywords: Wnt signalling; acute myeloid leukaemia; beta-catenin; small molecules.

Figure 1. Outline of canonical Wnt signalling

In the absence of a Wnt ligand bound to LRP and Frizzled receptors, β-catenin is bound by a destruction complex consisting of GSK3β, Axin, CK1 and APC. β-Catenin is phosphorylated leading to subsequent ubiquitination by βTrCP and degradation in the proteasome. Wnt target genes remain off as TCF is bound to the transcriptional repressor Groucho. Upon binding of a Wnt ligand to LRP/Frizzled the destruction complex is recruited to phosphorylated LRP through Axin where β-catenin is bound and phosphorylated. However, βTrCP can no longer ubiquitinate β-catenin causing saturation of the DC and subsequent stabilization of β-catenin which translocates to the nucleus, binds TCF/LEF, and activates Wnt target genes (created using Biorender).

Figure 2. Pharmacological targeting of β-catenin AML

Summary of the attempted and theoretical strategies used to therapeutically target oncogenic β-catenin stability an activity in AML cells. Compound abbreviations = CWP; CWP232291, CGP; CGP049090, PFK; PFK115-584, ICG; ICG-001, PRI; PRI-274, 5-AZA; 5-Aza-2′-deoxycytidine, PROTAC; Proteolysis-Targeting Chimaeras, MSAB; methyl 3-{[(4-methylphenyl)sulfonyl]amino} benzoate, SOR; Sorafenib, QUI; Quizartinib (created using Biorender).

Figure 3. β-Catenin interactions with RBPs in myeloid cells

Scatter plots showing RBP interactions detected in β-catenin interactomes performed in (A) K562 cytosolic, (B) K562 nuclear, (C) HEL cytosolic and (D) HEL nuclear fractions. Vertical dashed red line indicates the threshold for 2-fold change in protein binding at log₂ (= 1) relative to IgG co-IP. Horizontal red line represents threshold for significant interactions at P=0.05 on log₁₀ scale (= 1.3). Highlighted red dots indicate statistically significant interactions and green labels indicate RBPs. Combined GO term network demonstrating biological processes of β-catenin interacting proteins found in the (E) cytoplasmic and (F) nuclear fractions of HEL, HL60 and K562 cells. Nodes (circles) in the network represent GO terms associated with the β-catenin interacting proteins. Red nodes represent GO terms with relatively high adjusted enrichment P-values (i.e., P-value is close to 0.05 which indicates term is less accurate at representing a function or process associated with the gene list). Comparatively, white nodes indicate GO terms with lower P-values close to 0. Edges (lines between nodes) representing how closely related the GO terms are to one another, with thick lines representing closely related GO terms.