GSK-3 Promotes Conditional Association of CREB and Its Coactivators with MEIS1 to Facilitate HOX-Mediated Transcription and Oncogenesis

Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias. ► GSK-3 kinase activity maintains the MLL leukemia stem cell transcriptional program ► GSK-3 promotes the conditional association of MEIS1 with CREB and its coactivators ► Inhibition of GSK-3 targets HOX-associated transcriptional programs in MLL leukemias