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

Abstract

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.

Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms

“…In contrast to our dynamic study, Tong et al found, at one time point after IFNα treatment using Target-Seq, an increased quiescence in homozygous and apoptosis in heterozygous JAK2 V617F HSPC 38 . It is possible that such pathways could be found in the remaining non targeted JAK2 V617F HSPC at later time point or that several mechanisms such as senescence or apoptosis might cooperate to reinforce the HSC exhaustion 34,35,[37][38][39] . Characterizing such additional factors will require more experimental data coupled with a more sophisticated model.…”

Mouse models of myeloproliferative neoplasms for pre-clinical testing of novel therapeutic agents

“…The GFP reporter system combined with transgenic models of JAK2-V617F is reliable and can be applied also for testing combinations of drug treatment. Recently, this approach was used to show synergism between interferon-α and arsenic 77 .…”

A knockout combination for MPN stem cells

“…Molecular remissions appear to require prolonged treatment over a protracted time frame, and, therefore, it would be advantageous to determine combination strategies to further enhance this process in order to accelerate clinical responses. Importantly, Dagher et al now demonstrate that arsenic trioxide (ATO) enhances the effect of IFNα in the treatment of MPN by depleting Jak2 V617F mutant stem cell populations (Dagher et al, 2020).…”

“…Interestingly, PML has also been characterized as an IFN-stimulated gene (ISG;Stadler et al, 1995). These preliminary findings led Dagher et al (2020) to ask whether increased PML-NB formation may contribute to the efficacy of IFNα therapy in the treatment of MPN and, furthermore, whether this effect could be enhanced by combining IFNα with ATO. Dagher et al (2020) were able to show that IFNα treatment increased the number of PML-NBs in primary human MPN CD34 + cells and JAK2 V617F mutant human cell lines.…”

“…These preliminary findings led Dagher et al (2020) to ask whether increased PML-NB formation may contribute to the efficacy of IFNα therapy in the treatment of MPN and, furthermore, whether this effect could be enhanced by combining IFNα with ATO. Dagher et al (2020) were able to show that IFNα treatment increased the number of PML-NBs in primary human MPN CD34 + cells and JAK2 V617F mutant human cell lines. Interestingly, JAK2 mutant CD34 + cells isolated from MPN patients demonstrated an increased number of PML-NBs at baseline in comparison to wild type.…”