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Cancer Cell. 2010 Jun 15;17(6):597-608. doi: 10.1016/j.ccr.2010.04.024.

GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.

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1
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

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.

PMID:
20541704
PMCID:
PMC2919232
DOI:
10.1016/j.ccr.2010.04.024
[Indexed for MEDLINE]
Free PMC Article

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