Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia

B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ se...

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Autores principales: Wang, Xiang, Zhang, Xi, Li, Ben-shang, Zhai, Xiaowen, Yang, Zhuo, Ding, Li-xia, Wang, Hongsheng, Liang, Chris, Zhu, Weiliang, Ding, Jian, Meng, Ling-hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279406/
https://www.ncbi.nlm.nih.gov/pubmed/25313141
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author Wang, Xiang
Zhang, Xi
Li, Ben-shang
Zhai, Xiaowen
Yang, Zhuo
Ding, Li-xia
Wang, Hongsheng
Liang, Chris
Zhu, Weiliang
Ding, Jian
Meng, Ling-hua
author_facet Wang, Xiang
Zhang, Xi
Li, Ben-shang
Zhai, Xiaowen
Yang, Zhuo
Ding, Li-xia
Wang, Hongsheng
Liang, Chris
Zhu, Weiliang
Ding, Jian
Meng, Ling-hua
author_sort Wang, Xiang
collection PubMed
description B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.
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spelling pubmed-42794062015-01-06 Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia Wang, Xiang Zhang, Xi Li, Ben-shang Zhai, Xiaowen Yang, Zhuo Ding, Li-xia Wang, Hongsheng Liang, Chris Zhu, Weiliang Ding, Jian Meng, Ling-hua Oncotarget Research Paper B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy. Impact Journals LLC 2014-09-26 /pmc/articles/PMC4279406/ /pubmed/25313141 Text en Copyright: © 2014 Wang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wang, Xiang
Zhang, Xi
Li, Ben-shang
Zhai, Xiaowen
Yang, Zhuo
Ding, Li-xia
Wang, Hongsheng
Liang, Chris
Zhu, Weiliang
Ding, Jian
Meng, Ling-hua
Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title_full Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title_fullStr Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title_full_unstemmed Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title_short Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
title_sort simultaneous targeting of pi3kδ and a pi3kδ-dependent mek1/2-erk1/2 pathway for therapy in pediatric b-cell acute lymphoblastic leukemia
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279406/
https://www.ncbi.nlm.nih.gov/pubmed/25313141
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