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

Sevim, O.; Wagstaff, M.; Ling, R. E.; Goff, A.; Palmer, D.; Park, H.; Hills, K.; Blair, A.; Castellano, L.; Newbury, S. F.; Roy, A.; Towler, B. P.; Morgan, R. G.

doi:10.64898/2026.01.25.698240

bioRxiv · 10.64898/2026.01.25.698240

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

Sevim, O.·Wagstaff, M.·Ling, R. E.·Goff, A.·Palmer, D.·Park, H.·Hills, K.·Blair, A.·Castellano, L.·Newbury, S. F.·Roy, A.·Towler, B. P.·Morgan, R. G.

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Abstract

BackgroundWnt/{beta}-catenin signalling is dysregulated in acute myeloid leukaemia (AML), where it lacks effective targeting strategies. Previously, we discovered that {beta}-catenin interacts with several RNA-binding proteins (RBP), indicating post-transcriptional influence which is yet to be therapeutically interrogated in AML. MethodsCo-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 {beta}-catenin and LIN28B was tested through combinations of genetic and pharmacological inhibition in AML cells. ResultsThe most frequent RBP-binding motif amongst {beta}-catenin-bound mRNAs was the GGAG motif targeted by oncofetal miRNA-regulating RBP; LIN28B. {beta}-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 {beta}-catenin- and LIN28B-depleted myeloid cells revealed potential cooperative and antagonistic function in miRNA regulation. Finally, dual-targeting both {beta}-catenin and LIN28B through either genetic and/or pharmacological means preferentially reduced AML cell viability. ConclusionThe {beta}-catenin:LIN28B axis could represent a novel synthetically lethal relationship in AML which could be exploited in rare subtypes where LIN28B expression becomes reactivated.

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Sevim, O., Wagstaff, M., Ling, R. E., Goff, A., Palmer, D., Park, H., Hills, K., Blair, A., Castellano, L., Newbury, S. F., Roy, A., Towler, B. P., Morgan, R. G.. 2026-01-27. Dual targeting a LIN28B:β-catenin axis in acute myeloid leukaemia. https://doi.org/10.64898/2026.01.25.698240

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