Using conditional Pten-deficient T-ALL mouse model and NOTCH1-mutated disseminated T-ALL PDX models, which recapitulate several features of human T-ALL biology, we showed that disruption of the NOTCH1-MYC-CD44 axis interferes with the maintenance of leukemia by targeting the LIC population. The gene discussed is CD44; the disease is acute lymphoblastic leukemia.