Cargando…
Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia
Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of C...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886351/ https://www.ncbi.nlm.nih.gov/pubmed/33527899 http://dx.doi.org/10.7554/eLife.65905 |
_version_ | 1783651777395032064 |
---|---|
author | Takao, Sumiko Forbes, Lauren Uni, Masahiro Cheng, Shuyuan Pineda, Jose Mario Bello Tarumoto, Yusuke Cifani, Paolo Minuesa, Gerard Chen, Celine Kharas, Michael G Bradley, Robert K Vakoc, Christopher R Koche, Richard P Kentsis, Alex |
author_facet | Takao, Sumiko Forbes, Lauren Uni, Masahiro Cheng, Shuyuan Pineda, Jose Mario Bello Tarumoto, Yusuke Cifani, Paolo Minuesa, Gerard Chen, Celine Kharas, Michael G Bradley, Robert K Vakoc, Christopher R Koche, Richard P Kentsis, Alex |
author_sort | Takao, Sumiko |
collection | PubMed |
description | Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control. |
format | Online Article Text |
id | pubmed-7886351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-78863512021-02-18 Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia Takao, Sumiko Forbes, Lauren Uni, Masahiro Cheng, Shuyuan Pineda, Jose Mario Bello Tarumoto, Yusuke Cifani, Paolo Minuesa, Gerard Chen, Celine Kharas, Michael G Bradley, Robert K Vakoc, Christopher R Koche, Richard P Kentsis, Alex eLife Cancer Biology Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control. eLife Sciences Publications, Ltd 2021-02-02 /pmc/articles/PMC7886351/ /pubmed/33527899 http://dx.doi.org/10.7554/eLife.65905 Text en © 2021, Takao et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Takao, Sumiko Forbes, Lauren Uni, Masahiro Cheng, Shuyuan Pineda, Jose Mario Bello Tarumoto, Yusuke Cifani, Paolo Minuesa, Gerard Chen, Celine Kharas, Michael G Bradley, Robert K Vakoc, Christopher R Koche, Richard P Kentsis, Alex Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title | Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title_full | Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title_fullStr | Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title_full_unstemmed | Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title_short | Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia |
title_sort | convergent organization of aberrant myb complex controls oncogenic gene expression in acute myeloid leukemia |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886351/ https://www.ncbi.nlm.nih.gov/pubmed/33527899 http://dx.doi.org/10.7554/eLife.65905 |
work_keys_str_mv | AT takaosumiko convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT forbeslauren convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT unimasahiro convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT chengshuyuan convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT pinedajosemariobello convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT tarumotoyusuke convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT cifanipaolo convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT minuesagerard convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT chenceline convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT kharasmichaelg convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT bradleyrobertk convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT vakocchristopherr convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT kocherichardp convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia AT kentsisalex convergentorganizationofaberrantmybcomplexcontrolsoncogenicgeneexpressioninacutemyeloidleukemia |