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RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
- Source :
- J Clin Invest, JOURNAL OF CLINICAL INVESTIGATION
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
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 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00219738 and 15588238
- Database :
- OpenAIRE
- Journal :
- J Clin Invest, JOURNAL OF CLINICAL INVESTIGATION
- Accession number :
- edsair.doi.dedup.....7320b73d3d90f1b61255b31a6ace270f