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

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...

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Autores principales: Stankiewicz, Monika J., Crispino, John D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915509/
https://www.ncbi.nlm.nih.gov/pubmed/23380710
http://dx.doi.org/10.1038/leu.2013.33
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author Stankiewicz, Monika J.
Crispino, John D.
author_facet Stankiewicz, Monika J.
Crispino, John D.
author_sort Stankiewicz, Monika J.
collection PubMed
description 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 cross talk between AKT signaling and ERG in megakaryopoiesis. We discovered that constitutive AKT signaling is associated with a dramatic increase in apoptosis of WT MKs, but that overexpression of ERG blocks AKT-induced death. We further found that Gata1 mutations protect megakaryocytes from activated AKT-induced apoptosis. As a consequence, however, the enhanced signaling inhibits differentiation of Gata1 mutant, but not WT, megakaryocytes. 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 AMKL cell lines, AML with knockdown of FOXO3a, or AML with expression of myrAKT. 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 DS-TMD/AMKL indicates that AKT is a therapeutic target in this form of AML.
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spelling pubmed-39155092014-02-06 AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL Stankiewicz, Monika J. Crispino, John D. Leukemia Article 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 cross talk between AKT signaling and ERG in megakaryopoiesis. We discovered that constitutive AKT signaling is associated with a dramatic increase in apoptosis of WT MKs, but that overexpression of ERG blocks AKT-induced death. We further found that Gata1 mutations protect megakaryocytes from activated AKT-induced apoptosis. As a consequence, however, the enhanced signaling inhibits differentiation of Gata1 mutant, but not WT, megakaryocytes. 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 AMKL cell lines, AML with knockdown of FOXO3a, or AML with expression of myrAKT. 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 DS-TMD/AMKL indicates that AKT is a therapeutic target in this form of AML. 2013-02-05 2013-06 /pmc/articles/PMC3915509/ /pubmed/23380710 http://dx.doi.org/10.1038/leu.2013.33 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Stankiewicz, Monika J.
Crispino, John D.
AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title_full AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title_fullStr AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title_full_unstemmed AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title_short AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL
title_sort akt collaborates with erg and gata1s to dysregulate megakaryopoiesis and promote amkl
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915509/
https://www.ncbi.nlm.nih.gov/pubmed/23380710
http://dx.doi.org/10.1038/leu.2013.33
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