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Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia

Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of...

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Autores principales: DeKelver, Russell C., Lewin, Benjamin, Lam, Kentson, Komeno, Yukiko, Yan, Ming, Rundle, Chandler, Lo, Miao-Chia, Zhang, Dong-Er
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794898/
https://www.ncbi.nlm.nih.gov/pubmed/24130502
http://dx.doi.org/10.1371/journal.pgen.1003765
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author DeKelver, Russell C.
Lewin, Benjamin
Lam, Kentson
Komeno, Yukiko
Yan, Ming
Rundle, Chandler
Lo, Miao-Chia
Zhang, Dong-Er
author_facet DeKelver, Russell C.
Lewin, Benjamin
Lam, Kentson
Komeno, Yukiko
Yan, Ming
Rundle, Chandler
Lo, Miao-Chia
Zhang, Dong-Er
author_sort DeKelver, Russell C.
collection PubMed
description Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C(2)H(2) zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control.
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spelling pubmed-37948982013-10-15 Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia DeKelver, Russell C. Lewin, Benjamin Lam, Kentson Komeno, Yukiko Yan, Ming Rundle, Chandler Lo, Miao-Chia Zhang, Dong-Er PLoS Genet Research Article Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C(2)H(2) zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control. Public Library of Science 2013-10-10 /pmc/articles/PMC3794898/ /pubmed/24130502 http://dx.doi.org/10.1371/journal.pgen.1003765 Text en © 2013 DeKelver et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
DeKelver, Russell C.
Lewin, Benjamin
Lam, Kentson
Komeno, Yukiko
Yan, Ming
Rundle, Chandler
Lo, Miao-Chia
Zhang, Dong-Er
Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title_full Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title_fullStr Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title_full_unstemmed Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title_short Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia
title_sort cooperation between runx1-eto9a and novel transcriptional partner klf6 in upregulation of alox5 in acute myeloid leukemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794898/
https://www.ncbi.nlm.nih.gov/pubmed/24130502
http://dx.doi.org/10.1371/journal.pgen.1003765
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