JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML

J Exp Med. 2021 Feb 1;218(2):e20201268. doi: 10.1084/jem.20201268.


Interferon α (IFNα) is used to treat JAK2V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα 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 IFNα-induced growth suppression of JAK2V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenic Trioxide / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Interferon-alpha / pharmacology*
  • Janus Kinase 2 / metabolism*
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / metabolism
  • Promyelocytic Leukemia Protein / metabolism*


  • Interferon-alpha
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Arsenic Trioxide