RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
| العنوان: | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia |
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| المؤلفون: | 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 |
| المصدر: | J Clin Invest JOURNAL OF CLINICAL INVESTIGATION |
| بيانات النشر: | American Society for Clinical Investigation, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, CHEMOKINE RECEPTOR CXCR4, Core Binding Factor Alpha 1 Subunit, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, BETA-CATENIN, Mice, 0302 clinical medicine, Immunophenotyping, Medicine and Health Sciences, TRANSCRIPTION, Child, Gene Rearrangement, Organelle Biogenesis, GENE-EXPRESSION SIGNATURES, TARGETING SURVIVIN, Gene Expression Regulation, Developmental, Cell migration, General Medicine, LINEAGE, Gene Expression Regulation, Neoplastic, Chemotaxis, Leukocyte, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Progression, Stem cell, STEM-CELLS, Myeloid-Lymphoid Leukemia Protein, Research Article, Signal Transduction, Receptors, CXCR4, T cell, ACUTE MYELOID-LEUKEMIA, Biology, In Vitro Techniques, Core Binding Factor beta Subunit, OSTEOBLAST DIFFERENTIATION, 03 medical and health sciences, Downregulation and upregulation, stomatognathic system, Cell Line, Tumor, medicine, Animals, Humans, RNA, Messenger, Transcription factor, B cell, DRUG-RESISTANCE, Chemotaxis, Histone-Lysine N-Methyltransferase, Hematopoiesis, 030104 developmental biology, Cancer research |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0021-9738 1558-8238 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7320b73d3d90f1b61255b31a6ace270f https://europepmc.org/articles/PMC7954605/ |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7320b73d3d90f1b61255b31a6ace270f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219738 15588238 |
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