RUNX2 is a dependency factor in immature and KMT2A-rearranged T-cell acute lymphoblastic leukemia [KARPAS-45 RUNX2 shRNA knockdown 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 Examination of transcriptional changes upon RUNX2 shRNA mediated knockdown in the T-ALL cell line KARPAS-45. KARPAS-45 cells were transduced with shRUNX2-1 (TRCN 0000013653), shRUNX2-2 (TRCN 0000013655) or scrambled control (plko-shc002) and sampled 48 hours and 72 hours later. Data obtained from control was compared to pooled data from both RUNX2 specific hairpins for 5 independent experiments