TY - JOUR
T1 - RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
AU - Matthijssens, Filip
AU - Sharma, Nitesh D.
AU - Nysus, Monique
AU - Nickl, Christian K.
AU - Kang, Huining
AU - Perez, Dominique R.
AU - Lintermans, Beatrice
AU - Van Loocke, Wouter
AU - Roels, Juliette
AU - Peirs, Sofie
AU - Demoen, Lisa
AU - Pieters, Tim
AU - Reunes, Lindy
AU - Lammens, Tim
AU - De Moerloose, Barbara
AU - Van Nieuwerburgh, Filip
AU - Deforce, Dieter L.
AU - Cheung, Laurence C.
AU - Kotecha, Rishi S.
AU - Risseeuw, Martijn D.P.
AU - Van Calenbergh, Serge
AU - Takarada, Takeshi
AU - Yoneda, Yukio
AU - Van Delft, Frederik W.
AU - Lock, Richard B.
AU - Merkley, Seth D.
AU - Chigaev, Alexandre
AU - Sklar, Larry A.
AU - Mullighan, Charles G.
AU - Loh, Mignon L.
AU - Winter, Stuart S.
AU - Hunger, Stephen P.
AU - Goossens, Steven
AU - Castillo, Eliseo F.
AU - Ornatowski, Wojciech
AU - Van Vlierberghe, Pieter
AU - Matlawska-Wasowska, Ksenia
PY - 2021/3/15
Y1 - 2021/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102681763&partnerID=8YFLogxK
U2 - 10.1172/JCI141566
DO - 10.1172/JCI141566
M3 - Article
C2 - 33555272
AN - SCOPUS:85102681763
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
M1 - e141566
ER -