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dc.contributor.authorMatthijssens, Filip
dc.contributor.authorSharma, Nitesh D
dc.contributor.authorNysus, Monique
dc.contributor.authorNickl, Christian K
dc.contributor.authorKang, Huining
dc.contributor.authorPerez, Dominique R
dc.contributor.authorLintermans, Beatrice
dc.contributor.authorVan Loocke, Wouter
dc.contributor.authorRoels, Juliette
dc.contributor.authorPeirs, Sofie
dc.contributor.authorDemoen, Lisa
dc.contributor.authorPieters, Tim
dc.contributor.authorReunes, Lindy
dc.contributor.authorLammens, Tim
dc.contributor.authorDe Moerloose, Barbara
dc.contributor.authorVan Nieuwerburgh, Filip
dc.contributor.authorDeforce, Dieter L
dc.contributor.authorCheung, Laurence
dc.contributor.authorKotecha, Rishi
dc.contributor.authorRisseeuw, Martijn DP
dc.contributor.authorVan Calenbergh, Serge
dc.contributor.authorTakarada, Takeshi
dc.contributor.authorYoneda, Yukio
dc.contributor.authorvan Delft, Frederik W
dc.contributor.authorLock, Richard B
dc.contributor.authorMerkley, Seth D
dc.contributor.authorChigaev, Alexandre
dc.contributor.authorSklar, Larry A
dc.contributor.authorMullighan, Charles G
dc.contributor.authorLoh, Mignon L
dc.contributor.authorWinter, Stuart S
dc.contributor.authorHunger, Stephen P
dc.contributor.authorGoossens, Steven
dc.contributor.authorCastillo, Eliseo F
dc.contributor.authorOrnatowski, Wojciech
dc.contributor.authorVan Vlierberghe, Pieter
dc.contributor.authorMatlawska-Wasowska, Ksenia
dc.date.accessioned2021-02-26T05:56:12Z
dc.date.available2021-02-26T05:56:12Z
dc.date.issued2021
dc.identifier.citationMatthijssens, 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.urihttp://hdl.handle.net/20.500.11937/82712
dc.identifier.doi10.1172/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.languageeng
dc.relation.sponsoredbyhttp://purl.org/au-research/grants/nhmrc/1142627
dc.relation.sponsoredbyhttp://purl.org/au-research/grants/nhmrc/1059804
dc.relation.sponsoredbyhttp://purl.org/au-research/grants/nhmrc/1157871
dc.subjectCell migration/adhesion
dc.subjectLeukemias
dc.subjectMolecular biology
dc.subjectOncology
dc.titleRUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
dc.typeJournal Article
dcterms.source.issn0021-9738
dcterms.source.titleJournal of Clinical Investigation
dc.date.updated2021-02-26T05:56:11Z
curtin.note

Reproduced with permission from ASCI.

curtin.departmentCurtin Medical School
curtin.departmentSchool of Pharmacy and Biomedical Sciences
curtin.accessStatusOpen access
curtin.facultyFaculty of Health Sciences
curtin.contributor.orcidCheung, Laurence [0000-0001-6298-5288]
curtin.contributor.orcidKotecha, Rishi [0000-0003-1836-4075]
dcterms.source.eissn1558-8238
curtin.contributor.scopusauthoridCheung, Laurence [56663936300]


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