Factors in the microenvironment differentially impact the behavior of T-ALL cells. Some support leukemic cell expansion (IL18, IL7, CXCL12, IGF1 provided by dendritic cells), whereas others protect them against chemotherapy (adipose tissue and hypoxia). The work of Panelli et al reveals a noncanonical interaction between β-catenin and FOXO3. This interaction induces a gene expression signature typically found in a chemoresistant cell population expressing CD82 and CD117/receptor tyrosine kinase (KIT). These cells are found enriched in early T-ALL and MRD of T-ALL and are endowed with high capacity of leukemia initiation in immunodeficient mice. CDK4, cyclin-dependent kinase 4; Wnt, wingless-related integration site.