TY - JOUR
T1 - Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment
AU - Chen, Zhenghao
AU - Simon-Molas, Helga
AU - Cretenet, Gaspard
AU - Valle-Argos, Beatriz
AU - Smith, Lindsay D.
AU - Forconi, Francesco
AU - Schomakers, Bauke V.
AU - van Weeghel, Michel
AU - Bryant, Dean J.
AU - van Bruggen, Jaco A. C.
AU - Peters, Fleur S.
AU - Rathmell, Jeffrey C.
AU - van der Windt, Gerritje J. W.
AU - Kater, Arnon P.
AU - Packham, Graham
AU - Eldering, Eric
N1 - Funding Information: This work was supported by Netherlands Organization for Scientific Research/Netherlands Organization for Health Research and Development Veni grant 4600284662, Vidi grant 91715337, ERC Consolidator: BOOTCAMP (864815), Lymph and Co: 2018-LYCo-008, Cancer Center Amsterdam grant 2022 and Cancer Research UK grant C2750/A23669. Publisher Copyright: © 2022 American Society of Hematology
PY - 2022/8/11
Y1 - 2022/8/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85132192009&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood.2021013990
DO - https://doi.org/10.1182/blood.2021013990
M3 - Article
C2 - 35486832
SN - 0006-4971
VL - 140
SP - 630
EP - 643
JO - Blood
JF - Blood
IS - 6
ER -