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A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias
The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and pro...
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/PMC4297268/ https://www.ncbi.nlm.nih.gov/pubmed/25027513 http://dx.doi.org/10.1038/leu.2014.221 |
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author | Conway, Amanda E. Haldeman, Jonathan M. Wechsler, Daniel S. Lavau, Catherine P. |
author_facet | Conway, Amanda E. Haldeman, Jonathan M. Wechsler, Daniel S. Lavau, Catherine P. |
author_sort | Conway, Amanda E. |
collection | PubMed |
description | The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor. |
format | Online Article Text |
id | pubmed-4297268 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42972682015-08-01 A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias Conway, Amanda E. Haldeman, Jonathan M. Wechsler, Daniel S. Lavau, Catherine P. Leukemia Article The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor. 2014-07-16 2015-02 /pmc/articles/PMC4297268/ /pubmed/25027513 http://dx.doi.org/10.1038/leu.2014.221 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 Conway, Amanda E. Haldeman, Jonathan M. Wechsler, Daniel S. Lavau, Catherine P. A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title | A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title_full | A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title_fullStr | A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title_full_unstemmed | A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title_short | A Critical Role for CRM1 in Regulating HOXA Gene Transcription in CALM-AF10 Leukemias |
title_sort | critical role for crm1 in regulating hoxa gene transcription in calm-af10 leukemias |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297268/ https://www.ncbi.nlm.nih.gov/pubmed/25027513 http://dx.doi.org/10.1038/leu.2014.221 |
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