RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

Matthijssens, Filip; Sharma, Nitesh; Nysus, Monique; Nickl, Christian K.; Kang, Huining; Perez, Dominique; Lintermans, Béatrice; Loocke, Wouter Van; Roels, Juliette; Peirs, Sofie; Demoen, Lisa; Pieters, Tim; Reunes, Lindy; Lammens, Tim; Moerloose, Barbara De; Nieuwerburgh, Filip Van; Deforce, Dieter; Cheung, Laurence C.; Kotecha, Rishi S.; Risseeuw, Martijn; Calenbergh, Serge Van; Takarada, Takeshi; Yoneda, Yukio; Delft, Frederik W. van; Lock, Richard B.; Merkley, Seth D.; Chigaev, Alexandre; Sklar, Larry A.; Mullighan, Charles G.; Loh, Mignon L.; Winter, Stuart S.; Hunger, Stephen P.; Goossens, Steven; Castillo, Eliseo F.; Ornatowski, Wojciech; Vlierberghe, Pieter Van; Matławska-Wasowska, Ksenia

doi:10.1172/jci141566

Cited by 31 publications

(25 citation statements)

References 102 publications

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“…Our group reported upregulation of RUNX2 in primary T-ALL harboring KMT2A-rearrangements and immature/ETP phenotype. RUNX2 increased both, glycolytic and oxidative metabolism as well as the expression of critical regulators of mitochondrial dynamics and biogenesis in T-ALL cell lines (Matthijssens et al, 2021). Upregulation of RUNX2 increased metabolic potential of T-ALL cells and accelerated T-ALL progression and dissemination to the meninges as well as other organs.…”

Section: Krebs Cycle and Amino Acid Metabolismmentioning

confidence: 95%

“…Strong evidence suggests that leukemic cells have increased glycolysis (Warburg, 1956b;Boag et al, 2006;Herst et al, 2011;Calviño et al, 2014;Liu et al, 2014;Poulain et al, 2017;Robinson et al, 2020;Matthijssens et al, 2021). In line with this, Kato et al ( 2017) compared the transcriptome of B-cell acute lymphoblastic leukemia (B-ALL) cells derived from the CNS and BM of xenografted mice, and the BM and CSF of pediatric B-ALL patients with CNS disease.…”

Section: Glycolysismentioning

confidence: 99%

“…We recently reported that Runt-related transcription factor 2 (RUNX2) was upregulated in children, adolescents, and young adults with high-risk T-ALL and its increased expression was associated with leukemic cell migration and dissemination of T-ALL to extramedullary sites including the meninges (Matthijssens et al, 2021). RUNX2 potentiated T-ALL metabolic activity by enhancing ATP production and glycolysis in vitro.…”

Section: Glycolysismentioning

confidence: 99%

“…Specifically, RUNX2 induced LDHA, PGK1, and GLUT1 expression concomitant with an increase in glucose uptake and glycolysis. Treatment with 2DG, an inhibitor of glucose metabolism (hexokinase inhibitor), reduced T-ALL migration, indicating a potential role of glycolysis in RUNX2-mediated T-ALL cell chemotaxis (Matthijssens et al, 2021). Further studies are required to determine whether and how glycolysis affects the ability of leukemic cells to invade and survive in the CNS.…”

Section: Glycolysismentioning

confidence: 99%

“…Acute leukemias commonly display an increase in glucose uptake and aerobic glycolysis (Suganuma et al, 2010;Kishton et al, 2016;Matthijssens et al, 2021). In addition, enhanced mitochondrial respiration (OXPHOS) increases the reactive oxygen species (ROS) levels in leukemic cells (Han et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

Sharma

Keewan

Matławska-Wasowska

2021

Front. Cell Dev. Biol.

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Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.

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Section: Krebs Cycle and Amino Acid Metabolismmentioning

confidence: 95%