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 Dp 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 6 (03 15 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 33555272 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CBFB protein, human
• CXCR4 protein, human
• Core Binding Factor Alpha 1 Subunit
• Core Binding Factor beta Subunit
• KMT2A protein, human
• RNA, Messenger
• RUNX2 protein, human
• Receptors, CXCR4
• Myeloid-Lymphoid Leukemia Protein
• Histone-Lysine N-Methyltransferase

Topics

• Animals
• Cell Line, Tumor
• Chemotaxis, Leukocyte
• Child
• Core Binding Factor Alpha 1 Subunit (genetics, metabolism)
• Core Binding Factor beta Subunit (metabolism)
• Disease Progression
• Gene Expression Regulation, Developmental
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement
• Hematopoiesis
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• In Vitro Techniques
• Mice
• Myeloid-Lymphoid Leukemia Protein (genetics, metabolism)
• Organelle Biogenesis
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• Receptors, CXCR4 (metabolism)
• Signal Transduction