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.
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