Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.

T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including develo...

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Autores principales:	Stefan Nagel, Corinna Meyer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f72f6d61dfc44ff5bcbe1642e15402bf
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spelling	oai:doaj.org-article:f72f6d61dfc44ff5bcbe1642e15402bf2021-12-02T20:16:18ZEstablishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.1932-620310.1371/journal.pone.0259674https://doaj.org/article/f72f6d61dfc44ff5bcbe1642e15402bf2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0259674https://doaj.org/toc/1932-6203T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.Stefan NagelCorinna MeyerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0259674 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefan Nagel Corinna Meyer Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
description	T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.
format	article
author	Stefan Nagel Corinna Meyer
author_facet	Stefan Nagel Corinna Meyer
author_sort	Stefan Nagel
title	Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
title_short	Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
title_full	Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
title_fullStr	Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
title_full_unstemmed	Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.
title_sort	establishment of the tbx-code reveals aberrantly activated t-box gene tbx3 in hodgkin lymphoma.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f72f6d61dfc44ff5bcbe1642e15402bf
work_keys_str_mv	AT stefannagel establishmentofthetbxcoderevealsaberrantlyactivatedtboxgenetbx3inhodgkinlymphoma AT corinnameyer establishmentofthetbxcoderevealsaberrantlyactivatedtboxgenetbx3inhodgkinlymphoma
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Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma.

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