RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
Filip Matthijssens, … , Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska
Filip Matthijssens, … , Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska
Published February 8, 2021
Citation Information: J Clin Invest. 2021;131(6):e141566. https://doi.org/10.1172/JCI141566.
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Research Article Oncology

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

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.

Authors

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

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Figure 2

RUNX2 is highly expressed in ETPs, but has no major impact on phenotypic markers of normal hematopoiesis or T cell development.

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RUNX2 is highly expressed in ETPs, but has no major impact on phenotypi...
RUNX2 expression in human (A) and mouse (B) T cell subsets. (C) qRT-PCR for Runx2 expression in cKit-enriched and cKit-negative mouse thymocytes. Rel., relative. (D and E) Peripheral blood cell counts measured in Runx2fl/flVaviCre+/+ (Ctrl), Runx2fl/+VaviCretg/+ (Hez), and Runx2fl/flVaviCretg/+ (KO) mice (7–10 weeks). (F) Total cell number extracted from thymuses. (G–J) Percentages of T cell subsets measured by flow cytometry. (G) DP, double-negative T cells, (H) DN, double-positive T cells, (I) CD4 single-positive T cells, (J) CD8 single-positive T cells. (C) Paired 2-tailed t test; (D–J) 1-way ANOVA with Tukey’s multiple comparison test. ***P < 0.0005.