RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
dc.contributor.author | Matthijssens, Filip | |
dc.contributor.author | Sharma, Nitesh D | |
dc.contributor.author | Nysus, Monique | |
dc.contributor.author | Nickl, Christian K | |
dc.contributor.author | Kang, Huining | |
dc.contributor.author | Perez, Dominique R | |
dc.contributor.author | Lintermans, Beatrice | |
dc.contributor.author | Van Loocke, Wouter | |
dc.contributor.author | Roels, Juliette | |
dc.contributor.author | Peirs, Sofie | |
dc.contributor.author | Demoen, Lisa | |
dc.contributor.author | Pieters, Tim | |
dc.contributor.author | Reunes, Lindy | |
dc.contributor.author | Lammens, Tim | |
dc.contributor.author | De Moerloose, Barbara | |
dc.contributor.author | Van Nieuwerburgh, Filip | |
dc.contributor.author | Deforce, Dieter L | |
dc.contributor.author | Cheung, Laurence | |
dc.contributor.author | Kotecha, Rishi | |
dc.contributor.author | Risseeuw, Martijn DP | |
dc.contributor.author | Van Calenbergh, Serge | |
dc.contributor.author | Takarada, Takeshi | |
dc.contributor.author | Yoneda, Yukio | |
dc.contributor.author | van Delft, Frederik W | |
dc.contributor.author | Lock, Richard B | |
dc.contributor.author | Merkley, Seth D | |
dc.contributor.author | Chigaev, Alexandre | |
dc.contributor.author | Sklar, Larry A | |
dc.contributor.author | Mullighan, Charles G | |
dc.contributor.author | Loh, Mignon L | |
dc.contributor.author | Winter, Stuart S | |
dc.contributor.author | Hunger, Stephen P | |
dc.contributor.author | Goossens, Steven | |
dc.contributor.author | Castillo, Eliseo F | |
dc.contributor.author | Ornatowski, Wojciech | |
dc.contributor.author | Van Vlierberghe, Pieter | |
dc.contributor.author | Matlawska-Wasowska, Ksenia | |
dc.date.accessioned | 2021-02-26T05:56:12Z | |
dc.date.available | 2021-02-26T05:56:12Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Matthijssens, F. and Sharma, N.D. and Nysus, M. and Nickl, C.K. and Kang, H. and Perez, D.R. and Lintermans, B. et al. 2021. RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. Journal of Clinical Investigation. 131 (6): Article No. e141566. | |
dc.identifier.uri | http://hdl.handle.net/20.500.11937/82712 | |
dc.identifier.doi | 10.1172/JCI141566 | |
dc.description.abstract |
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed 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 reported 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 demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration. | |
dc.language | eng | |
dc.relation.sponsoredby | http://purl.org/au-research/grants/nhmrc/1142627 | |
dc.relation.sponsoredby | http://purl.org/au-research/grants/nhmrc/1059804 | |
dc.relation.sponsoredby | http://purl.org/au-research/grants/nhmrc/1157871 | |
dc.subject | Cell migration/adhesion | |
dc.subject | Leukemias | |
dc.subject | Molecular biology | |
dc.subject | Oncology | |
dc.title | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. | |
dc.type | Journal Article | |
dcterms.source.issn | 0021-9738 | |
dcterms.source.title | Journal of Clinical Investigation | |
dc.date.updated | 2021-02-26T05:56:11Z | |
curtin.note |
Reproduced with permission from ASCI. | |
curtin.department | Curtin Medical School | |
curtin.department | School of Pharmacy and Biomedical Sciences | |
curtin.accessStatus | Open access | |
curtin.faculty | Faculty of Health Sciences | |
curtin.contributor.orcid | Cheung, Laurence [0000-0001-6298-5288] | |
curtin.contributor.orcid | Kotecha, Rishi [0000-0003-1836-4075] | |
dcterms.source.eissn | 1558-8238 | |
curtin.contributor.scopusauthorid | Cheung, Laurence [56663936300] |