ULK1 as a novel therapeutic target in Myeloproliferative Neoplasms
We provide evidence that genetic or pharmacological targeting of ULK1 delays disease progression in Jak2V617F-mutant MPN in vivo models. Mechanistically, the ULK1 anti-neoplastic effects were found to be associated, at least in part, with the transcriptional regulation of genes involved in myeloid malignancies and hematopoietic stem cell differentiation, leading to a reduced number of early-stage erythroid progenitors in both spleen and bone marrow, decreased levels of hemoglobin, hematocrit and red blood cells and spleen size in MPN in vivo models. These findings reveal a novel pro-tumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling characteristic of MPNs and highlight the potential of targeting this kinase as a new therapeutic strategy for MPN patients. Overall design: HEL cells were treated with either vehicle (DMSO), 5mM of ULK101 or 5mM of SBI-0206965 for 4 hours and assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed.