GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis
- PMID: 20541704
- PMCID: PMC2919232
- 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
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.
Copyright 2010 Elsevier Inc. All rights reserved.
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Comment in
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Glycogen synthase kinase-3 and leukemia: restoring the balance.Cancer Cell. 2010 Jun 15;17(6):529-31. doi: 10.1016/j.ccr.2010.05.017. Cancer Cell. 2010. PMID: 20541696 Free PMC article.
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Leukaemia: MLL makes friends and influences.Nat Rev Cancer. 2010 Aug;10(8):529. doi: 10.1038/nrc2904. Nat Rev Cancer. 2010. PMID: 20677349 No abstract available.
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