Leukemia stem cells (LSCs)resist elimination by tyrosine kinase inhibitor (TKI)treatment. Bhatia and colleagues report that CXCL12 deletion from mesenchymal stromal cells (MSCs)reduces LSC colocalization, enhances LSC cycling, and increases LSC elimination by TKI treatment, indicating that CXCL12-expressing MSC niches are critical for maintaining quiescent, TKI-resistant LSCs.