Fig. 1 Base editor screen identifies asciminib resistance in ABL1 SH3, SH2, and kinase domains

Figure 1 outlines a high-throughput adenosine base editor (ABE) screen designed to map asciminib resistance hotspots across the BCR::ABL1 protein. After transducing K562 cells with a tiling sgRNA library and applying asciminib selection for nine days, the screen revealed significant resistance-conferring mutations distributed broadly across the SH3, SH2, and kinase domains. The top enriched guides, which included both known mutations and novel discoveries like Y139C and E505G, were functionally validated to maintain high-level resistance even at supraphysiological asciminib concentrations up to 1000 nM. Mapping these functionally confirmed hits allowed for the identification of specific, highly resistant hotspots across the protein, which were then prioritized for high-resolution follow-up using deep mutational scanning.