Targeting the MYC and PI3K pathways eliminates leukemia-initiating cells in T cell acute lymphoblastic leukemia
Menée à l'aide d'un modèle murin génétiquement modifié de leucémie aiguë lymphoblastique T, cette étude met en évidence le rôle joué par les cellules initiatrices de leucémie dans la résistance thérapeutique
Disease relapse remains the major clinical challenge in treating T cell acute lymphoblastic leukemia (T-ALL), particularly those with PTEN loss. We hypothesized that leukemia-initiating cells (LICs) are responsible for T-ALL development and treatment relapse. In this study, we used a genetically engineered mouse model of Pten-/- T-ALL with defined blast and LIC-enriched cell populations to demonstrate that LICs are responsible for therapeutic resistance. Unlike acute and chronic myelogenous leukemia, LICs in T-ALL were actively cycling, were distinct biologically and responded differently to targeted therapies in comparison to their differentiated blast cell progeny. Notably, we found that T-ALL LICs could be eliminated by co-targeting the deregulated pathways driven by phosphoinositide 3-kinase (PI3K) and Myc, which are altered commonly in human T-ALL and are associated with LIC formation. Our findings define critical events that may be targeted to eliminate LICs in T-ALL as a new strategy to treat the most aggressive relapsed forms of this disease.