Meis1 supports leukemogenesis through stimulation of ribosomal biogenesis and Myc

Abstract

The homeobox transcription factors HoxA9 and Meis1 are causally involved in the etiology of acute myeloid leukemia. While HoxA9 immortalizes cells, cooperation with Meis1 is necessary to induce malignancy. Here, we apply degron techniques to elucidate the leukemogenic contribution of Meis1. ChIP-seq demonstrated that Meis1 localized mainly to H3K27ac and H3K4me1 modified enhancers pre-bound by HoxA9. HoxA9 was epistatic to Meis1 as degradation of HoxA9 caused an immediate release of Meis1 from chromatin. Nascent-RNA sequencing revealed the Meis1 gene expression pattern to be dominated by Myc, ribosome biogenesis and rRNA synthesis. While Myc accounted for cell-cycle stimulation, it could not substitute the leukemogenic effects of Meis1. Enhanced ribosomal biogenesis was accompanied by elevated resistance against RNA polymerase I and translation blocking inhibitors without affecting steady-state protein synthesis. HoxA9 and Meis1 protein stability was controlled by casein kinase 2 (CK2). CK2 inhibition caused rapid degradation of HoxA9 and Meis1 suggesting a potentially exploitable regulatory pathway.