Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia.

Autor:	Rodems BJ; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA., Sharma S; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA., Baker CD; Genomics Research Center, University of Rochester Medical Center, Rochester, NY 14642, USA., Kaszuba CM; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA., Ito T; Department of Bioscience and Technology, Graduate School of Bioscience and Technology, Fukui Prefectural University, Fukui, Japan., Liesveld JL; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Division of Hematology and Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA., Calvi LM; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA., Becker MW; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Division of Hematology and Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA., Jordan CT; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Ashton JM; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Genomics Research Center, University of Rochester Medical Center, Rochester, NY 14642, USA., Bajaj J; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 14. Date of Electronic Publication: 2024 May 14.
DOI:	10.1101/2024.05.11.593633
Abstrakt:	Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified 1-6 , concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map 7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemias in vivo by downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax 8, 9 to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.
Databáze:	MEDLINE
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