Jak2(V617f) Myeloproliferative Neoplasm Eradication By A Novel Interferon/Arsenic Therapy Involves Pml

Interferon alpha (IFN alpha) is used to treat JAK2(V617F)-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFN alpha mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFN alpha-induced growth suppression of JAK2(V617F) patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFN alpha enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFN alpha+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.