Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL).

2.50
Hdl Handle:
http://hdl.handle.net/10033/249355
Title:
Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL).
Authors:
Nagel, Stefan; Ehrentraut, Stefan; Tomasch, Jürgen; Lienenklaus, Stefan; Schneider, Björn; Geffers, Robert; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F
Abstract:
Homeobox genes encode transcription factors impacting key developmental processes including embryogenesis, organogenesis, and cell differentiation. Reflecting their tight transcriptional control, homeobox genes are often embedded in large non-coding, cis-regulatory regions, containing tissue specific elements. In T-cell acute lymphoblastic leukemia (T-ALL) homeobox genes are frequently deregulated by chromosomal aberrations, notably translocations adding T-cell specific activatory elements. NKX3-1 is a prostate specific homeobox gene activated in T-ALL patients expressing oncogenic TAL1 or displaying immature T-cell characteristics. After investigating regulation of NKX3-1 in primary cells and cell lines, we report its ectopic expression in T-ALL cells independent of chromosomal rearrangements. Using siRNAs and expression profiling, we exploited NKX3-1 positive T-ALL cell lines as tools to investigate aberrant activatory mechanisms. Our data confirmed NKX3-1 activation by TAL1/GATA3/LMO and identified LYL1 as an alternative activator in immature T-ALL cells devoid of GATA3. Moreover, we showed that NKX3-1 is directly activated by early T-cell homeodomain factor MSX2. These activators were regulated by MLL and/or by IL7-, BMP4- and IGF2-signalling. Finally, we demonstrated homeobox gene SIX6 as a direct leukemic target of NKX3-1 in T-ALL. In conclusion, we identified three major mechanisms of NKX3-1 regulation in T-ALL cell lines which are represented by activators TAL1, LYL1 and MSX2, corresponding to particular T-ALL subtypes described in patients. These results may contribute to the understanding of leukemic transcriptional networks underlying disturbed T-cell differentiation in T-ALL.
Affiliation:
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
Citation:
Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL). 2012, 7 (7):e40747 PLoS ONE
Journal:
PloS one
Issue Date:
2012
URI:
http://hdl.handle.net/10033/249355
DOI:
10.1371/journal.pone.0040747
PubMed ID:
22848398
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publikations of the AG Genomanalytik(GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorNagel, Stefanen_GB
dc.contributor.authorEhrentraut, Stefanen_GB
dc.contributor.authorTomasch, Jürgenen_GB
dc.contributor.authorLienenklaus, Stefanen_GB
dc.contributor.authorSchneider, Björnen_GB
dc.contributor.authorGeffers, Roberten_GB
dc.contributor.authorMeyer, Corinnaen_GB
dc.contributor.authorKaufmann, Marenen_GB
dc.contributor.authorDrexler, Hans Gen_GB
dc.contributor.authorMacLeod, Roderick A Fen_GB
dc.date.accessioned2012-10-18T11:18:19Z-
dc.date.available2012-10-18T11:18:19Z-
dc.date.issued2012-
dc.identifier.citationTranscriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL). 2012, 7 (7):e40747 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid22848398-
dc.identifier.doi10.1371/journal.pone.0040747-
dc.identifier.urihttp://hdl.handle.net/10033/249355-
dc.description.abstractHomeobox genes encode transcription factors impacting key developmental processes including embryogenesis, organogenesis, and cell differentiation. Reflecting their tight transcriptional control, homeobox genes are often embedded in large non-coding, cis-regulatory regions, containing tissue specific elements. In T-cell acute lymphoblastic leukemia (T-ALL) homeobox genes are frequently deregulated by chromosomal aberrations, notably translocations adding T-cell specific activatory elements. NKX3-1 is a prostate specific homeobox gene activated in T-ALL patients expressing oncogenic TAL1 or displaying immature T-cell characteristics. After investigating regulation of NKX3-1 in primary cells and cell lines, we report its ectopic expression in T-ALL cells independent of chromosomal rearrangements. Using siRNAs and expression profiling, we exploited NKX3-1 positive T-ALL cell lines as tools to investigate aberrant activatory mechanisms. Our data confirmed NKX3-1 activation by TAL1/GATA3/LMO and identified LYL1 as an alternative activator in immature T-ALL cells devoid of GATA3. Moreover, we showed that NKX3-1 is directly activated by early T-cell homeodomain factor MSX2. These activators were regulated by MLL and/or by IL7-, BMP4- and IGF2-signalling. Finally, we demonstrated homeobox gene SIX6 as a direct leukemic target of NKX3-1 in T-ALL. In conclusion, we identified three major mechanisms of NKX3-1 regulation in T-ALL cell lines which are represented by activators TAL1, LYL1 and MSX2, corresponding to particular T-ALL subtypes described in patients. These results may contribute to the understanding of leukemic transcriptional networks underlying disturbed T-cell differentiation in T-ALL.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.titleTranscriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL).en
dc.typeArticleen
dc.contributor.departmentDepartment of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.deen_GB
dc.identifier.journalPloS oneen_GB

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