Increased mTOR activation in idiopathic multicentric Castleman disease.
Adolescent
Adult
Aged
Biomarkers, Tumor
/ metabolism
Case-Control Studies
Castleman Disease
/ metabolism
Child
Child, Preschool
Cohort Studies
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Infant
Interleukin-6
/ metabolism
Male
Middle Aged
Prognosis
Proteome
/ analysis
Ribosomal Protein S6 Kinases
/ metabolism
Signal Transduction
TOR Serine-Threonine Kinases
/ metabolism
Young Adult
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
07 05 2020
07 05 2020
Historique:
received:
06
08
2019
accepted:
03
02
2020
pubmed:
25
3
2020
medline:
1
1
2021
entrez:
25
3
2020
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 32206779
pii: S0006-4971(20)62048-1
doi: 10.1182/blood.2019002792
pmc: PMC7205815
doi:
Substances chimiques
Biomarkers, Tumor
0
Interleukin-6
0
Proteome
0
MTOR protein, human
EC 2.7.1.1
Ribosomal Protein S6 Kinases
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT03933904']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1673-1684Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL141408
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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