Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia
Menée in vitro et à l'aide de modèles murins, cette étude étude met en évidence l'intérêt d'inhiber la voie de signalisation JAK/STAT et la déméthylsase LSD1 pour traiter une leucémie myéloïde aiguë avec mutation des gènes CSF3R/CEBPA
Acute myeloid leukemia is a blood cancer that has poor outcomes with conventional treatment. The clinical behavior of the disease is driven in large part by the gene mutations that are responsible for disease development. The combination of mutations in the genes CEBPA and CSF3R is associated with an increased risk of recurrent disease after standard therapy. We have identified a drug combination that blocks signaling through the JAK/STAT pathway and inhibits the epigenetic regulator LSD1. This drug combination leads to maturation of immature leukemia cells and improves survival in mouse models in a synergistic manner. This therapeutic approach is a promising strategy for the treatment of AML patients with mutations in CEBPA and CSF3R.Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.