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

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• The t(1;22) translocation creates the RBM15-MKL1 (RM) fusion protein in acute megakaryoblastic leukemia (AMKL).
• N6-methyladenosine (m6A) RNA modification is crucial for RNA fate and implicated in cancer.
• RBM15 normally recruits the m6A writer complex to target RNAs.

Purpose of the Study:

• To investigate if the RM fusion protein disrupts m6A modification and drives leukemogenesis in RM-AMKL.
• To identify specific RNA targets and pathways regulated by RM-induced m6A changes.
• To evaluate the therapeutic potential of targeting m6A modification in RM-AMKL.

Main Methods:

• Multiomics approach to analyze RNA targets and m6A modification.
• Treatment of murine RM-AMKL cells with a METTL3 inhibitor (STM3675).
• Assessment of apoptosis, cell survival, and gene expression changes.
• Frizzled gene knockdown in vitro and in vivo.

Main Results:

• RM retains RBM15's RNA-binding and m6A-modifying functions but targets distinct RNAs, including Frizzled genes in the Wnt pathway.
• METTL3 inhibition decreased m6A deposition, induced apoptosis in RM-AMKL cells, and prolonged survival in mice.
• Frizzled genes were upregulated by RM and downregulated by METTL3 inhibition, suggesting m6A-dependent regulation.
• Frizzled knockdown inhibited RM-AMKL growth, confirming Wnt signaling's oncogenic role.

Conclusions:

• RM-specific m6A modifications and Wnt pathway activation are critical drivers of RM-AMKL.
• Targeting METTL3 or the Wnt pathway presents a potential therapeutic strategy for RM-AMKL.