Increased mTOR activation in idiopathic multicentric Castleman disease
Open accessAbstract
Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).
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Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting in idiopathic multicentric Castleman's disease include CXCL13, CXCL10, VEGF-A, type I interferon, mTORC1, and JAK-STAT3.
“Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting include CXCL13, CXCL10 (interferon-inducible protein 10 [IP-10]), VEGF-A,82 type I interferon,83 mTOR complex 1 (mTORC1),84 and JAK-STAT3.”
From Cytokine storm (2020) · cites this paper as [84]
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- Authors
- Arenas, D. J., Floess, K., Kobrin, D., Pai, R.-A. L., Srkalovic, M. B., Tamakloe, M.-A., Rasheed, R., Ziglar, J., Khor, J., Parente, S. A. T., Pierson, S. K., Martinez, D., Wertheim, G. B., Kambayashi, T., Baur, J., Teachey, D. T., & Fajgenbaum, D. C.
- Affiliations
- University of Pennsylvania (US)
- Department of Pathology and
- Children's Hospital of Philadelphia (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2020-05-07
- Volume
- 135
- Issue
- 19
- Pages
- 1673-1684
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC7205815
- OpenAlex
- W3012641818
- Cited by
- 83
- References
- 55
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 16 · 2023: 10 · 2022: 20 · 2021: 15 · 2020: 6
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health (2r01hl141408-06)
- National Heart, Lung, and Blood Institute (R01-HL141408, HL141408)
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- idiopathic multicentric Castleman disease, mTOR signaling, mTORC1, rapamycin, interleukin-6, serum proteome, lymph node histopathology, pS6, p4EBP1, p70S6K, JAK1/2 inhibition, monocytes, T cells, therapeutic target
- MeSH terms
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Castleman Disease, Humans, Infant, Male, Middle Aged, Prognosis, Biomarkers, Tumor, Cohort Studies, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, Case-Control Studies, Ribosomal Protein S6 Kinases, Proteome, Young Adult, TOR Serine-Threonine Kinases
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