Dual targeting a LIN28B:β-catenin axis in acute myeloid leukaemia

Background Wnt/β-catenin signalling is dysregulated in acute myeloid leukaemia (AML), where it lacks effective targeting strategies. Previously, we discovered that β-catenin interacts with several RNA-binding proteins (RBP), indicating post-transcriptional influence which is yet to be therapeutically interrogated in AML.

Co-immunoprecipitation confirmed protein interactions, and TCF/LEF reporters were used to assess Wnt signalling output in leukaemia cells. Regulatory crosstalk was assessed using immunoblotting and RT-qPCR approaches following lentiviral transduction of myeloid cell lines. Targeting of β-catenin and LIN28B was tested through combinations of genetic and pharmacological inhibition in AML cells.

The most frequent RBP-binding motif amongst β-catenin-bound mRNAs was the GGAG motif targeted by oncofetal miRNA-regulating RBP; LIN28B. β-Catenin:LIN28B interactions were detected in lymphoid and myeloid cell lines, plus primary human CD34⁺ fetal-liver HSCs. LIN28B positively regulated Wnt signalling output through LEF1 regulation involving a post-transcriptional let7 miRNA mechanism. Further miRNA sequencing of β-catenin- and LIN28B-depleted myeloid cells revealed potential cooperative and antagonistic function in miRNA regulation. Finally, dual-targeting both β-catenin and LIN28B through either genetic and/or pharmacological means preferentially reduced AML cell viability.

The β-catenin:LIN28B axis could represent a novel synthetically lethal relationship in AML which could be exploited in rare subtypes where LIN28B expression becomes reactivated. Competing Interest Statement The authors have declared no competing interest. Footnotes Manuscript reformatted, and data extended over 6 figures to align with target journal submission.