| First Author | Saleiro D | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 1750 |
| PubMed ID | 35365653 | Mgi Jnum | J:323886 |
| Mgi Id | MGI:7263874 | Doi | 10.1038/s41467-022-29381-7 |
| Citation | Saleiro D, et al. (2022) Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms. Nat Commun 13(1):1750 |
| abstractText | Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNalpha 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 IFNalpha and others do not. Here, we identify and characterize a pathway involving PKCdelta-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 IFNalpha therapy in these patients. We also demonstrate that IFNalpha 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. |
