Partial differentiation induction of leukemia cells co-opts NK cells to erode leukemic stemness

ATRA-induced granulocytic differentiation of acute promyelocytic leukemia (APL) cells is thought to underpin high-rate cure of this disease. Yet, how differentiation induction affects leukemic stemness remains undetermined. To address this, we employed flow cytometry- and scRNA-seq-based leukemic subset dissection and functional assays to characterize APL hierarchy, revealing a particular structure wherein apical leukemic progenitors underwent multitiered and lineage-branching differentiation into monocytic and/or granulocytic directions, which was dynamically modulated by different treatments. Notably, ATRA shifted APL hierarchy towards granulocytic differentiation but inefficiently generated terminal granulocytes, leaving relative persistence of intermediate differentiating subsets that retained certain leukemia-initiating cell (LIC) potential. Nevertheless, ATRA rendered most of the intermediate c-Kit ^−/lo granulocytic LICs more vulnerable to endogenous CD62L ⁺ NK subset-mediated immunorejection. Thus, our observations demonstrate that ATRA-triggered LIC erosion critically depends on NK immunity rather than on APL cells’ entry into terminal maturation.