These results suggest that MDS patients receiving venetoclax-based therapy should be monitored closely for the acquisition or expansion of clones with STAG2 or RUNX1 mutations and enrolled in clinical trials of agents targeting NF-κB signaling effectors, such as MCL1, before their disease undergoes HSC transcriptional reprogramming and becomes resistant to venetoclax. Here, RUNX1 is linked to myelodysplastic syndrome.