# Signal Transduction of Type 1 Interferons in Malignant Cells

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $358,500

## Abstract

PROJECT SUMMARY/ABSTRACT
This is a competing renewal application whose overall objective is to define the mechanisms of interferon (IFN)-
signaling in malignant cells. We have provided the first evidence for the existence of a novel pathway engaged
by the Type I IFN receptor (IFNR), involving the ULK1 kinase. This ULK1 pathway operates in an autophagy-
independent manner to regulate expression of IFN stimulated genes (ISGs) and is essential for the generation
of the suppressive effects of IFNon primary malignant hematopoietic precursors from patients with
myeloproliferative neoplasms (MPNs). Remarkably, ULK1 forms complexes with unique partners that have
distinct structures and functional capabilities, suggesting that coordinated operation of such complexes is
required for optimal control of IFN-induced antineoplastic effects. Aim 1 will identify upstream IFNR-generated
signals and mechanisms that control ULK1 activation. It includes studies to map the IFN-phosphorylation sites
on ULK1 and identify direct upstream kinases that modify its function. Aim 2 will define ULK1 effector pathways
that mediate IFN-responses. It includes experiments to determine the roles of novel effectors that we have
identified, including ROCK1/2, PCM1 and CARD9. A combination of approaches will be used, including
generation of selective knockouts by the CRISPR-Cas9 methodology and mutation of putative ULK1
phosphorylation sites in the structures of target proteins, followed by assessment of its effects on IFN signaling
and antineoplastic responses. Aim 3 will define the role of ULK1 pathways in the generation of the antineoplastic
effects of IFN in MPNs. Jak2V617F-driven MPN mouse models will be established using mice with Ulk1-/-,
Pcm1-/-, or Card9-/- backgrounds, and the ability of IFN to induce antineoplastic responses in such mice will be
examined. The therapeutic effects of a ROCK1/2 pharmacological inhibitor alone and in combination with
IFNin mediating anti-MPN responses in vivo will be also determined. In other studies, the activation of IFN-
dependent ULK1 effector signals will be determined in primary malignant precursors from patients with different
MPNs participating in IFN-clinical trials and correlated with molecular characteristics and clinical responses to
IFN-treatment. Altogether, this proposal introduces highly novel concepts in the IFN-field and the mechanisms
of IFN-generated antitumor effects and may lead to the development of novel therapeutic strategies and
approaches for the treatment of MPNs.

## Key facts

- **NIH application ID:** 10134255
- **Project number:** 5R01CA077816-21
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** LEONIDAS C. PLATANIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,500
- **Award type:** 5
- **Project period:** 1998-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134255

## Citation

> US National Institutes of Health, RePORTER application 10134255, Signal Transduction of Type 1 Interferons in Malignant Cells (5R01CA077816-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134255. Licensed CC0.

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