Back to Search Start Over

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

Authors :
Barbara De Moerloose
Serge Van Calenbergh
Wojciech Ornatowski
Steven Goossens
Sofie Peirs
Alexandre Chigaev
Wouter Van Loocke
Charles G. Mullighan
Pieter Van Vlierberghe
Christian K. Nickl
Takeshi Takarada
Mignon L. Loh
Eliseo F. Castillo
Laurence C. Cheung
Dominique Perez
Béatrice Lintermans
Yukio Yoneda
Frederik W. van Delft
Richard B. Lock
Stuart S. Winter
Juliette Roels
Stephen P. Hunger
Lisa Demoen
Lindy Reunes
Ksenia Matlawska-Wasowska
Larry A. Sklar
Monique Nysus
Rishi S. Kotecha
Tim Lammens
Huining Kang
Dieter Deforce
Tim Pieters
Nitesh D. Sharma
Filip Van Nieuwerburgh
Martijn D. P. Risseeuw
Seth D. Merkley
Filip Matthijssens
Source :
J Clin Invest, JOURNAL OF CLINICAL INVESTIGATION
Publication Year :
2021
Publisher :
American Society for Clinical Investigation, 2021.

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 CBF beta. 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.

Details

Language :
English
ISSN :
00219738 and 15588238
Database :
OpenAIRE
Journal :
J Clin Invest, JOURNAL OF CLINICAL INVESTIGATION
Accession number :
edsair.doi.dedup.....7320b73d3d90f1b61255b31a6ace270f