Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells

In this study, we show that targeted deletion of CXCL12 from mesenchymal stromal cells (MSC) reduces normal HSC numbers, but in contrast expands murine LSC numbers by increasing self-renewing cell divisions, related to enhanced EZH2 activity. CML development leads to emergence of abnormal niches of MSC and LSC clusters that are lost upon CXCL12 deletion. Importantly, CXCL12 deletion from MSC also increases LSC elimination by TKI treatment. These studies reveal a critical role for CXCL12-expressing MSC niches in maintaining a population of quiescent, TKI-resistant LSC, and support targeting of these niche interactions to enhance LSC elimination. LTHSC were sorted from the bone marrow of Cre-negative (No Cre), Tek-Cre, and Prx1-Cre mice directly into RLT buffer and RNA prepared, with four biological replicates from each group.