MEIS1-HLF axis regulates oxidative metabolism and is essential for MLL-fusion gene leukemia

The pathogenesis of MLL-fusion gene leukemias has been linked to upregulated expression of HOX genes and of the HOX-cofactor Meis1.The functions of the HOX/MEIS1 complex in leukemia however remain unclear. Here, we used inducible MEIS1-knockout mice coupled with MLL-AF9 knockin mice to decipher the role of MEIS1 in leukemia. We found that MEIS1 was critically required for established leukemia. Further, MEIS1 loss led to increased oxygen flux and apoptosis, while hypoxia reversed these effects. Finally, we identify HLF as a downstream mediator of MEIS1 in leukemia. Overexpression of HLF prevents oxygen flux and rescues the leukemia phenotype in MEIS1-deficient cells. Thus, the oncogenic effects of MEIS1 are at least partly mediated by an HLF-driven hypoxic state. Overall design: Mouse bone marrow MLL-AF9 knockin cells of conditional Meis1f/f or control genotypes were treated with vehicle or 1000 nM of 4-hydroxy tamoxifen for 24 hours in IMDM with 10% FBA and 10 ng/ml of murine GM-CSF, IL-3, IL-6, SCF. RNA was isolated from treated cells and submitted to gene expression and sequencing core of Cincinnati Children''s Hospital & Medical Center. A total of four samples were included, and two groups were assisgned. Comparison comprises mRNA expression profile of vehicle and 4-OHT treatment in control cells versus Meis1-deleted cells.

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Roychoudhury J, Clark JP, Gracia-Maldonado G, Unnisa Z, Wunderlich M, Link KA, Dasgupta N, Aronow B, Huang G, Mulloy JC, Kumar AR