Myeloblastosis proto-oncogene pre-messenger RNA (MYB pre-mRNA)

The Myeloblastosis proto-oncogene (MYB) pre-messenger RNA is the primary transcript of the MYB gene, which encodes a transcription factor essential for the maintenance and differentiation of hematopoietic stem cells (Ramsay & Gonda, 2008, Nature Reviews Cancer). MYB is frequently dysregulated in human cancers, particularly through overexpression in acute myeloid leukemia (AML) and the formation of the MYB-NFIB fusion gene in adenoid cystic carcinoma (ACC) (Persson et al., 2009, Proc Natl Acad Sci). Because the MYB protein lacks a traditional small-molecule binding pocket, it is considered "undruggable" by conventional means, leading to the development of therapies that target its pre-mRNA instead. Current therapeutic strategies include small molecule splicing modulators like REM-422, which induce the inclusion of a "poison exon" to trigger nonsense-mediated decay, and antisense oligonucleotides (ASOs) like ION-251 that promote RNase H-mediated degradation (Ward et al., 2021, Science Translational Medicine). By reducing the pool of available pre-mRNA, these agents effectively downregulate the production of the oncogenic MYB protein, leading to cell cycle arrest and apoptosis in malignant cells. However, a significant challenge in targeting MYB pre-mRNA is the potential for dose-limiting myelosuppression, as normal hematopoiesis also depends on MYB activity. Clinical trials are currently evaluating these RNA-targeted approaches in patients with relapsed or refractory leukemias and solid tumors (NCT06297941, NCT06118086).

Other names

c-Myb pre-mRNAProto-oncogene c-Myb pre-mRNAMYB precursor mRNA

Induction of poison exon inclusion leading to nonsense-mediated decay (NMD) and RNase H-mediated degradation of the pre-mRNA transcript.