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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...

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Autores principales: Conway, Amanda E., Haldeman, Jonathan M., Wechsler, Daniel S., Lavau, Catherine P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
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.
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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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