TY - JOUR
T1 - Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia
AU - Galán-Díez, Marta
AU - Borot, Florence
AU - Ali, Abdullah Mahmood
AU - Zhao, Junfei
AU - Gil-Iturbe, Eva
AU - Shan, Xiaochuan
AU - Luo, Na
AU - Liu, Yongfeng
AU - Huang, Xi Ping
AU - Bisikirska, Brygida
AU - Labella, Rossella
AU - Kurland, Irwin
AU - Roth, Bryan L.
AU - Quick, Matthias
AU - Mukherjee, Siddhartha
AU - Rabadán, Raul
AU - Carroll, Martin
AU - Raza, Azra
AU - Kousteni, Stavroula
N1 - Funding Information:
M. Galán-Díez reports grants from Mandl Connective Tissue Research Fellowship during the conduct of the study. F. Borot reports other support from Vor Biopharma outside the submitted work; is a coinventor on issued patents and pending patent applications filed by Columbia University and exclusively licensed to Vor Biopharma and has received distributions of proceeds from the license granted by Columbia University to Vor Biopharma; and has been a consultant for Vor Biopharma. B.L. Roth reports grants from the NIH during the conduct of the study. S. Kousteni reports grants from the NIH/NIAMS, NIH/NHLBI, Edward P. Evans Foundation for MDS Research, and NIH/NCI during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
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. Fernández, PhD, for metabolomic data analysis and critical discussion; and G. Karsenty, MD, PhD, and E. Passegué, 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. Galán-Díez; 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
Publisher Copyright:
©2022 The Authors.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85128160955&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-21-0692
DO - 10.1158/2159-8290.CD-21-0692
M3 - Article
C2 - 35046097
AN - SCOPUS:85128160955
SN - 2159-8274
VL - 12
SP - 1106
EP - 1127
JO - Cancer Discovery
JF - Cancer Discovery
IS - 4
ER -
