Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment.

Autor:	Chen Z; Experimental Immunology, and.; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands., Simon-Molas H; Experimental Immunology, and.; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands., Cretenet G; Experimental Immunology, and.; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands., Valle-Argos B; Curve Therapeutics, University of Southampton, Southampton, UK.; Cancer Research UK Centre, Cancer Sciences, University of Southampton, Southampton, UK., Smith LD; Cancer Research UK Centre, Cancer Sciences, University of Southampton, Southampton, UK.; Ploughshare Innovations Limited, Porton Science Park, Porton Down, UK., Forconi F; Department of Haematology, Southampton University Hospital Trust, Southampton, UK., Schomakers BV; Laboratory Genetic Metabolic Diseases, and.; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., van Weeghel M; Laboratory Genetic Metabolic Diseases, and.; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., Bryant DJ; Cancer Research UK Centre, Cancer Sciences, University of Southampton, Southampton, UK., van Bruggen JAC; Experimental Immunology, and.; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands., Peters FS; Experimental Immunology, and.; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands., Rathmell JC; Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., van der Windt GJW; Genmab, Utrecht, The Netherlands; and., Kater AP; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center, Amsterdam, The Netherlands., Packham G; Cancer Research UK Centre, Cancer Sciences, University of Southampton, Southampton, UK., Eldering E; Experimental Immunology, and.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Aug 11; Vol. 140 (6), pp. 630-643.
DOI:	10.1182/blood.2021013990
Abstrakt:	Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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