Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms

Diana Saleiro, Jeremy Q. Wen, Ewa M. Kosciuczuk, Frank Eckerdt, Elspeth M. Beauchamp, Chidera V. Oku, Gavin T. Blyth, Mariafausta Fischietti, Liliana Ilut, Marco Colamonici, William Palivos, Paula A. Atsaves, Dean Tan, Masha Kocherginsky, Rona Singer Weinberg, Eleanor N. Fish, John D. Crispino, Ronald Hoffman and Leonidas C. Platanias ()
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Diana Saleiro: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Jeremy Q. Wen: Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University
Ewa M. Kosciuczuk: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Frank Eckerdt: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Elspeth M. Beauchamp: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chidera V. Oku: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Gavin T. Blyth: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Mariafausta Fischietti: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Liliana Ilut: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Marco Colamonici: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
William Palivos: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Paula A. Atsaves: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Dean Tan: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Masha Kocherginsky: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Rona Singer Weinberg: New York Blood Center
Eleanor N. Fish: Toronto General Hospital Research Institute, University Health Network & Department of Immunology, University of Toronto
John D. Crispino: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Ronald Hoffman: Myeloproliferative Neoplasms Research Consortium
Leonidas C. Platanias: Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29381-7

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