Differential inflammatory conditioning of the bone marrow by acute myeloid leukemia and its impact on progression.
Blood Adv
; 8(19): 4983-4996, 2024 Oct 08.
Article
em En
| MEDLINE
| ID: mdl-38996202
ABSTRACT
ABSTRACT Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may affect leukemia is less well studied. Using annexin A5 (ANXA5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) vs chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor α (TNF-α) dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases ß-catenin and hypoxia-inducible factor 1α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML than other hematologic malignancies. Furthermore, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 [COX2]), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared with cytarabine alone. Taken together, TNF-α/ANXA5/NF-κB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and patients with AML with "inflammatory AML" may benefit from antiphlogistic agents as adjunct therapy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Medula Óssea
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Dinoprostona
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Leucemia Mieloide Aguda
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Progressão da Doença
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Inflamação
Limite:
Animals
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Humans
Idioma:
En
Revista:
Blood Adv
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Alemanha