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Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia
Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant PI3K-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139485/ https://www.ncbi.nlm.nih.gov/pubmed/24552990 http://dx.doi.org/10.1038/leu.2014.78 |
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author | Reynolds, Christine Roderick, Justine E. LaBelle, James L. Bird, Gregory Mathieu, Ronald Bodaar, Kimberly Colon, Diana Pyati, Ujwal Stevenson, Kristen E. Qi, Jun Harris, Marian Silverman, Lewis B. Sallan, Stephen E. Bradner, James E. Neuberg, Donna S. Look, A. Thomas Walensky, Loren D. Kelliher, Michelle A. Gutierrez, Alejandro |
author_facet | Reynolds, Christine Roderick, Justine E. LaBelle, James L. Bird, Gregory Mathieu, Ronald Bodaar, Kimberly Colon, Diana Pyati, Ujwal Stevenson, Kristen E. Qi, Jun Harris, Marian Silverman, Lewis B. Sallan, Stephen E. Bradner, James E. Neuberg, Donna S. Look, A. Thomas Walensky, Loren D. Kelliher, Michelle A. Gutierrez, Alejandro |
author_sort | Reynolds, Christine |
collection | PubMed |
description | Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant PI3K-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment- resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T- ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes, and in 33% of bim homozygous mutants (P = 0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL. |
format | Online Article Text |
id | pubmed-4139485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41394852015-03-01 Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia Reynolds, Christine Roderick, Justine E. LaBelle, James L. Bird, Gregory Mathieu, Ronald Bodaar, Kimberly Colon, Diana Pyati, Ujwal Stevenson, Kristen E. Qi, Jun Harris, Marian Silverman, Lewis B. Sallan, Stephen E. Bradner, James E. Neuberg, Donna S. Look, A. Thomas Walensky, Loren D. Kelliher, Michelle A. Gutierrez, Alejandro Leukemia Article Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant PI3K-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment- resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T- ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes, and in 33% of bim homozygous mutants (P = 0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL. 2014-02-20 2014-09 /pmc/articles/PMC4139485/ /pubmed/24552990 http://dx.doi.org/10.1038/leu.2014.78 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download 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 Reynolds, Christine Roderick, Justine E. LaBelle, James L. Bird, Gregory Mathieu, Ronald Bodaar, Kimberly Colon, Diana Pyati, Ujwal Stevenson, Kristen E. Qi, Jun Harris, Marian Silverman, Lewis B. Sallan, Stephen E. Bradner, James E. Neuberg, Donna S. Look, A. Thomas Walensky, Loren D. Kelliher, Michelle A. Gutierrez, Alejandro Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title | Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title_full | Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title_fullStr | Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title_full_unstemmed | Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title_short | Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia |
title_sort | repression of bim mediates survival signaling by myc and akt in high-risk t-cell acute lymphoblastic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139485/ https://www.ncbi.nlm.nih.gov/pubmed/24552990 http://dx.doi.org/10.1038/leu.2014.78 |
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