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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...

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Autores principales: 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
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
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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.
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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
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