RUNX2 is a dependency factor in immature and KMT2A-rearranged T-cell acute lymphoblastic leukemia [KMT2A-MLLT1_ Runx2 ko RNA-seq]

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a high incidence of relapse. Here we show that Runt-related transcription factor 2, RUNX2 is upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or immature phenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, while it reciprocally binds the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 is required for survival in immature and KMT2A-R T-ALL in vitro and in vivo. We report a direct transcriptional regulation of CXCR4 signaling by RUNX2, which thereby promotes cell migration and adhesion. Functionally, RUNX2 impacts T-ALL cell homing and exacerbates T-ALL progression to medullary and extramedullary sites. We demonstrate that RUNX2 enables these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation results in increased mitochondrial dynamics and biogenesis in T-ALL cells. As a proof of concept, immature and KMT2A-R T-ALL cells are vulnerable to pharmacological targeting of the interaction of RUNX2 with its co-factor CBFβ. In conclusion, we identify RUNX2 a dependency factor in immature and KMT2A-R T-ALL that regulates cell metabolism and disease progression