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We thank Rene Hen, PhD, for the Htr1b^-/- mice; P. Greengard, PhD, for Htr1bfl/fl mice; Roshan P. Shah, MD, for healthy patient samples; Mark Heany, MD, for AML samples; Yunping Qiu for technical assistance with metabolomic analysis; Michael P. Biagiotti for technical assistance with CRISPR/Cas9 assays; Israel S. Fernandez, PhD, for metabolomic data analysis and critical discussion; and G. Karsenty, MD, PhD, and E. Passegue, PhD, for critical review and comments. We thank the Columbia Stem Cell Initiative Flow Cytometry core facility (directed by Michael Kissner). Funding for this research was provided by NIH AR054447, HL130937, the Edward P. Evans Foundation for MDS Research to S. Kousteni, and the Mandl Connective Tissue Research Fellowship awarded to M. Galan-Diez; NIH/NCI Cancer Center Support Grant P30CA013696 and the Stable Isotope and Metabolomics Core Facility of the Diabetes Research and Training Center (DRTC) of the Albert Einstein College of Medicine (NIH P60DK020541). The Oncology Precision Therapeutics and Imaging Core (OPTIC) at the Herbert Irving Comprehensive Cancer Center at Columbia University shared resource was used.

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

Publicated to:Cancer Discovery. 12 (4): 1106-1127 - 2022-04-01 12(4), DOI: 10.1158/2159-8290.cd-21-0692

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

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Abstract

Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell non autonomous 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 proinfl ammatory 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. 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.

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