Characterizing the impact of MLL fusion variants and fusion partners on leukemia plasticity using a human CRISPR-engineered MLL-rearranged leukemia model

cells from the same donor. Compared to healthy control cells, all MLL-rearranged cells showed increased proliferation and stemness, as well as an altered immunophenotype characterized by the upregulation of leukemic markers. Transcriptomic profiling revealed breakpoint- and partner-specific gene expression patterns that influence the characteristics of the disease. Notably, even after prolonged in vitro culture MLL(intron 9)::AF9 cells displayed robust colony formation in semisolid media and engrafted robustly in NOD scid gamma mice. The cells still exhibited high lineage plasticity, switching from a myeloid to a B-lymphoid identity in vivo. In conclusion, this model enables the mechanistic dissection of MLL fusion variants in vitro and in vivo, providing a foundation for developing targeted therapies for MLL-rearranged leukemias.