Identifing AML niche
The retention of leukemic stem cells (LSCs) within the bone marrow (BM) microenvironment, known as the niche, significantly influences therapeutic resistance and leukemia relapse. Despite its importance, our understanding of the specific location of LSCs within the BM, the niche cells supporting their existence, and the intricate cross-talk between these elements remains incomplete. In this study, utilizing synergistic acute myeloid leukemia (AML) mouse models, we discovered that N-cadherin-expressing BM stromal cells (N-cad+ BMSCs) play a crucial role in influencing the localization of AML stem cells (SC) within central marrow or metaphysis areas. This localization is essential for their migration, stemness, and survival. Furthermore, we identified a significant interplay between the cell membrane proteins dipeptidyl peptidase 4 (DPP4) on AML cells and glypican-3 (GPC3) on N-cad+ BMSCs, regulating the activity and gradient of C-X-C motif chemokine ligand 12 (Cxcl12). These findings shed light on an unexplored aspect of Cxcl12-mediated crosstalk between LSCs and the two distinct LSC niches, namely the metaphysis niche and central marrow niche. The insights gained from this study provide a foundation for potential clinical therapies that involve manipulating LSC trafficking and retention.