Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia

Marta Galán-Díez, Florence Borot, Abdullah Mahmood Ali, Junfei Zhao, Eva Gil-Iturbe, Xiaochuan Shan, Na Luo, Yongfeng Liu, Xi Ping Huang, Brygida Bisikirska, Rossella Labella, Irwin Kurland, Bryan L. Roth, Matthias Quick, Siddhartha Mukherjee, Raul Rabadán, Martin Carroll, Azra Raza, Stavroula Kousteni

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 AMLsecreted 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 ratelimiting 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. SIGNIFICANCE: 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.

Original languageEnglish (US)
Pages (from-to)1106-1127
Number of pages22
JournalCancer discovery
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2022

ASJC Scopus subject areas

  • Oncology

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