RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation Free

• RM retains functional abilities of RBM15 and additionally interacts with Wnt-related transcripts to increase expression of Fzd proteins

• The METTL3 writer complex and WNT signalling pathways are essential for RM-driven leukemia

Acute megakaryoblastic leukemia driven by the RBM15-MKL1 fusion protein (RM-AMKL) is encoded by the recurrent t(1;22) translocation. Dysregulation of m6A modification affects RNA fate and is linked to oncogenesis. Because RBM15 is critical for bringing the m6A writer complex to specific RNAs, we hypothesized that RM disrupts m6A modification, altering RNA fate to drive leukemogenesis in RM-AMKL. Using a multi-omic approach, we show for the first time that RM retains the RNA-binding and m6A-modifying functions of RBM15 while also selectively regulating distinct mRNA targets including Frizzled genes in the WNT signaling pathway. Treating murine RM-AMKL cells with the METTL3 inhibitor STM3675, which decreases m6A deposition, induced apoptosis in vitro and prolonged survival in transplanted mice. Frizzled genes were upregulated by RM and downregulated upon METTL3 inhibition, implicating an m6A-dependent mechanism for their dysregulation. Direct Frizzled knockdown reduced RM-AMKL growth in vitro and in vivo, highlighting Wnt signaling as a key oncogenic driver. Elevated Wnt pathway and Frizzled expression in multiple forms of human AMKL underscores the relevance of our findings. Together, our results establish RM-specific m6A modifications and Wnt pathway activation as critical drivers of RM-AMKL, identifying these pathways as potential therapeutic targets.