Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
01 04 2022
01 04 2022
Historique:
received:
27
05
2021
revised:
08
11
2021
accepted:
04
01
2022
pubmed:
21
1
2022
medline:
6
4
2022
entrez:
20
1
2022
Statut:
ppublish
Résumé
Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1-the rate-limiting enzyme for kynurenine synthesis-thereby enabling AML progression. This leukemia-osteoblast cross-talk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment. AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine-HTR1B-SAA-IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873.
Identifiants
pubmed: 35046097
pii: 2159-8290.CD-21-0692
doi: 10.1158/2159-8290.CD-21-0692
pmc: PMC8983599
mid: NIHMS1773186
doi:
Substances chimiques
Kynurenine
343-65-7
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
1106-1127Subventions
Organisme : NIAMS NIH HHS
ID : R56 AR054447
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR054447
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020541
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR077152
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130937
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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