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; Leonidas C. Platanias

doi:10.1038/s41467-022-29381-7

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, Leonidas C. Platanias^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Article number	1750
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29381-7
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Saleiro, D., Wen, J. Q., Kosciuczuk, E. M., Eckerdt, F., Beauchamp, E. M., Oku, C. V., Blyth, G. T., Fischietti, M., Ilut, L., Colamonici, M., Palivos, W., Atsaves, P. A., Tan, D., Kocherginsky, M., Weinberg, R. S., Fish, E. N., Crispino, J. D., Hoffman, R., & Platanias, L. C. (2022). Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms. Nature communications, 13(1), Article 1750. https://doi.org/10.1038/s41467-022-29381-7

@article{74c94e9b5374481999d7c6b41f4c8cd5,

title = "Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms",

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.",

author = "Diana Saleiro and Wen, {Jeremy Q.} and Kosciuczuk, {Ewa M.} and Frank Eckerdt and Beauchamp, {Elspeth M.} and Oku, {Chidera V.} and Blyth, {Gavin T.} and Mariafausta Fischietti and Liliana Ilut and Marco Colamonici and William Palivos and Atsaves, {Paula A.} and Dean Tan and Masha Kocherginsky and Weinberg, {Rona Singer} and Fish, {Eleanor N.} and Crispino, {John D.} and Ronald Hoffman and Platanias, {Leonidas C.}",

note = "Funding Information: MPN patient samples were provided by the MPN Research Consortium, supported by National Cancer Institute P01CA108671. We thank C. B. Thompson (Memorial Sloan-Kettering Cancer Center) for the Ulk1/2 and Ulk1/2 MEFs. We thank PharmaEssentia for the murine ropeginterferon alpha. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. This work was supported by grants R01-CA77816 (LCP), R01-CA121192 (LCP), I01-CX000916 (LCP), R50-CA211534 (JQW), R01-CA237039 (JDC), R21-CA245447 (DS), a grant by the MPN Research Foundation (LCP) and support by the Vassilatos foundation (LCP). +/+ −/− Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-29381-7",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Saleiro, D, Wen, JQ, Kosciuczuk, EM, Eckerdt, F , Beauchamp, EM, Oku, CV, Blyth, GT, Fischietti, M, Ilut, L, Colamonici, M, Palivos, W, Atsaves, PA, Tan, D, Kocherginsky, M, Weinberg, RS, Fish, EN, Crispino, JD, Hoffman, R & Platanias, LC 2022, 'Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms', Nature communications, vol. 13, no. 1, 1750. https://doi.org/10.1038/s41467-022-29381-7

TY - JOUR

T1 - Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms

AU - Saleiro, Diana

AU - Wen, Jeremy Q.

AU - Kosciuczuk, Ewa M.

AU - Eckerdt, Frank

AU - Beauchamp, Elspeth M.

AU - Oku, Chidera V.

AU - Blyth, Gavin T.

AU - Fischietti, Mariafausta

AU - Ilut, Liliana

AU - Colamonici, Marco

AU - Palivos, William

AU - Atsaves, Paula A.

AU - Tan, Dean

AU - Kocherginsky, Masha

AU - Weinberg, Rona Singer

AU - Fish, Eleanor N.

AU - Crispino, John D.

AU - Hoffman, Ronald

AU - Platanias, Leonidas C.

N1 - Funding Information: MPN patient samples were provided by the MPN Research Consortium, supported by National Cancer Institute P01CA108671. We thank C. B. Thompson (Memorial Sloan-Kettering Cancer Center) for the Ulk1/2 and Ulk1/2 MEFs. We thank PharmaEssentia for the murine ropeginterferon alpha. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. This work was supported by grants R01-CA77816 (LCP), R01-CA121192 (LCP), I01-CX000916 (LCP), R50-CA211534 (JQW), R01-CA237039 (JDC), R21-CA245447 (DS), a grant by the MPN Research Foundation (LCP) and support by the Vassilatos foundation (LCP). +/+ −/− Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85127380963&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29381-7

DO - 10.1038/s41467-022-29381-7

M3 - Article

C2 - 35365653

AN - SCOPUS:85127380963

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1750

ER -

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

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