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Wnt/β-catenin signalling is dysregulated across several haematological malignancies, including acute myeloid leukaemia (AML), where is lacks effective targeting strategies. Previously, we discovered that β-catenin interacts with several RNA-binding proteins (RBP), and binds mRNA indirectly, indicating contributions to the post-transcriptional landscape of leukaemia cells. Here, we found the most frequent RBP-binding motif amongst β-catenin-bound mRNAs was the GGAG motif targeted by the oncofoetal expressed miRNA-regulating RBP LIN28B. We detected the β-catenin:LIN28B interaction in lymphoid and myeloid cell lines, and primary human CD34⁺ fetal liver-derived haematopoietic stem cells. LIN28B positively regulated Wnt signalling capacity by regulating LEF1 expression through a post-transcriptional mechanism requiring the let7 miRNA axis. Further miRNA sequencing of β-catenin- and LIN28B-depleted myeloid cells revealed both potential cooperative and antagonistic function in miRNA regulation. Finally, dual-targeting both β-catenin and LIN28B through either genetic or pharmacological means preferentially killed AML cells. These data reveal a potential novel synthetically lethal relationship in AML which could be exploited in the rare AML subsets where LIN28B expression becomes reactivated ### Competing Interest Statement The authors have declared no competing interest. Kay Kendall Leukaemia Fund, https://ror.org/03j2wfg84, KKL1051, KKL1446 Leukaemia & Myeloma Research UK, 4-5/06.21R Childrens Cancer & Leukaemia Group, CCLGA 2023 16 Morgan Republic of Türkiye Ministry of National Education