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Transcriptional Control and Signal Transduction

AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL

Leukemia volume 27, pages 1339–1347 (2013)Cite this article

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Abstract

The requirement that leukemic Gata1 mutations be present in cells harboring trisomy 21 led to the discovery that overexpression of ERG drives aberrant megakaryopoiesis. Given that constitutive PI3K/AKT signaling is a frequent component of hematologic malignancies and the relationship between AKT and Notch in this lineage, we studied the crosstalk between AKT signaling and ERG in megakaryopoiesis. We discovered that constitutive AKT signaling is associated with a dramatic increase in apoptosis of WT megakaryocytes (MKs), but that overexpression of ERG blocks AKT-induced death. We further found that Gata1 mutations protect MKs from activated AKT-induced apoptosis. As a consequence, however, the enhanced signaling inhibits differentiation of Gata1 mutant, but not WT, MKs. Gata1 mutant cells that overexpress ERG with hyperactive AKT are characterized by diminished FOXO1/3a expression and an increased dependency on the c-Jun pathway similar to that seen in acute megakaryoblastic leukemia (AMKL) cell lines, acute myeloid leukemia (AML) with knockdown of FOXO3a, or AML with expression of myristoylated Akt. Additionally, we found that the AKT allosteric inhibitor MK2206 caused reduced cell viability and proliferation of AMKL cell lines. The contribution of aberrant AKT signaling during the ontogeny of Down syndrome-transient myeloproliferative disorder/AMKL indicates that AKT is a therapeutic target in this form of AML.

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Acknowledgements

We are grateful to Thomas Mercher for plasmids and Merck for supplying MK2206 and thank the Robert H. Lurie Comprehensive Cancer Center supported Flow Cytometry Core and Cell Imaging Cores at Northwestern University. We also thank Benjamin Goldenson for assistance with CalcuSyn software calculations. This work was supported in part by the Samuel Waxman Cancer Research Foundation and a grant from the NCI (R01CA101774).

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  1. Department of Medicine, Northwestern University, Chicago, IL, USA

    M J Stankiewicz & J D Crispino

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  1. M J Stankiewicz
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Correspondence to J D Crispino.

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Stankiewicz, M., Crispino, J. AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL. Leukemia 27, 1339–1347 (2013). https://doi.org/10.1038/leu.2013.33

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