Discovery of a signaling feedback circuit that defines interferon responses in MPN

[Manouche]

« Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs »

nature.com/articles/s41467-...

[Pat032018]

Thanks Manouche. While I do not understand most of the explanation, I am encouraged by the findings that could lead to even better treatment in the future and I quote "These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs "

[EPguy]

Good progress toward the mysteries of INF response/ non-response.

Very deep molecular details. Thanks as usual for the latest reports.

As in your summary, having more "ULK1 and p38 MAPK" and less "ROCK1/2" is good for INF success. The two items are related: <<caspase-dependent cleavage/activation of ROCK1/2, which interacts with ULK1, .. >> so maybe cutting Rock adds ULK to control both factors.

For reducing Rock1/2 <<To date, the ROCK inhibitors Fasudil and Ripasudil are approved in Japan for the treatment of cerebral vasospasm and glaucoma, respectively, and several ROCK inhibitors are being tested clinically for the treatment of different diseases, including cancer>>

So we may soon have option to measure and if needed, improve our INF response, if/when Drs decide to try this method.

[MPort]

While I don't understand most it either the focus of the research and the possible options it offers gives me hope. Thank you for posting it.

[FG251]

Whilst I also didn’t get beyond the first sentence, the first sentence was enough!

[MPNBlog]

Hi Manouche, thanks for the posting. I think this may be the first paper I've seen that attempts to explain why some people respond to interferons and some don't. That was one of the purposes of "The Interferon Initiative". But I didn't ever see any research outcomes from that project that gave any answers. This article is the very early stages of research, but hopefully something of use to patients comes out of it eventually. Best wishes.