Parthenolide eliminates leukemia initiating cell populations and improves survival in xenografts of childhood acute lymphoblastic leukemia
Menée in vitro et à l'aide de xénogreffes, cette étude évalue les effets du parthénolide sur les cellules souches de leucémies pédiatriques
Around 20% of children with acute lymphoblastic leukemia (ALL) relapse due to failure to eradicate the disease. Current drug efficacy studies focus on reducing leukemia cell burden. However, if drugs have limited effects on leukemia-initiating cells (LIC), these cells may expand and eventually cause relapse. Parthenolide (PTL) has been shown to cause apoptosis of LIC in acute myeloid leukemia. Here, we assessed the effects of PTL on LIC populations in childhood ALL. Apoptosis assays demonstrated that PTL was effective against bulk B- and T-ALL cells, while the CD34+/CD19-, CD34+/CD7- and CD34- subpopulations were more resistant. However, functional analyses revealed that PTL treatment prevented engraftment of multiple LIC populations in NSG mice. PTL treatment of mice with established leukemias from low- and high-risk cases resulted in survival and restoration of normal murine hemopoiesis. In 3 cases only, disease progression was significantly slowed in mice engrafted with CD34+/CD19- or CD34+/CD7- and CD34- cells but not prevented, demonstrating that individual LIC populations within patients have different responses to therapy. These observations indicate that PTL may have therapeutic potential in childhood ALL and provide a basis for developing effective therapies that eradicate all LIC populations to prevent disease progression and reduce relapse.