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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2005-2-17
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pubmed:abstractText |
Activating fetal liver tyrosine kinase 3 (Flt3) mutations represent the most common genetic aberrations in acute myeloid leukemia (AML). Most commonly, they occur as internal tandem duplications in the juxtamembrane domain (Flt3-ITD) that transform myeloid cells in vitro and in vivo and that induce aberrant signaling and biologic functions. We identified RGS2, a regulator of G-protein signaling, as a gene specifically repressed by Flt3-ITD. Here we demonstrate an important role of RGS2 in Flt3-ITD-mediated transformation. RGS2 was repressed after forced expression of activating Flt3 mutations in 2 myeloid cell lines (32Dcl3 and NB4). Furthermore, RGS2 was repressed in Flt3-mutation-positive AML cases in comparison to Flt3-mutation-negative cases, especially in Flt3-ITD-positive cases with a high ITD-to-wild-type (WT) ratio. Coexpression of RGS2 with Flt3-ITD inhibited Flt3-ITD-induced autonomous proliferation and clonal growth of 32D cells. RGS2 also inhibited Flt3-ITD-induced phosphorylation of Akt and glycogen synthase kinase beta (Gsk3-beta) without influencing signal transducer and activator of transcription 5 (STAT5) activation. In addition, RGS2 reinduced the expression of Flt3-ITD-repressed CCAAT/enhancer-binding protein alpha (c/EBPalpha) and antagonized the Flt3-ITD-induced differentiation block in 32D cells. Expression analyses in myeloid cell lines revealed induction of RGS2 during granulocytic but not during monocytic differentiation. Taken together, RGS2 is a novel mediator of myeloid differentiation, and its repression is an important event in Flt3-ITD-induced transformation.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AKT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/RGS Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RGS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 beta
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:BerdelWolfgang EWE,
pubmed-author:BrandtsChristianC,
pubmed-author:ChoudharyChunaramC,
pubmed-author:Müller-TidowCarstenC,
pubmed-author:RehageMaikeM,
pubmed-author:RudatAnnikaA,
pubmed-author:SarginBülentB,
pubmed-author:SchwäbleJoachimJ,
pubmed-author:ServeHubertH,
pubmed-author:SteurClaudiaC,
pubmed-author:ThiedeChristianC,
pubmed-author:TickenbrockLaraL
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
105
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2107-14
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:15536149-Acute Disease,
pubmed-meshheading:15536149-Cell Differentiation,
pubmed-meshheading:15536149-Cell Line,
pubmed-meshheading:15536149-Cell Proliferation,
pubmed-meshheading:15536149-Cell Transformation, Neoplastic,
pubmed-meshheading:15536149-Glycogen Synthase Kinase 3,
pubmed-meshheading:15536149-HL-60 Cells,
pubmed-meshheading:15536149-Humans,
pubmed-meshheading:15536149-Leukemia, Myeloid,
pubmed-meshheading:15536149-Mutation,
pubmed-meshheading:15536149-Myeloid Cells,
pubmed-meshheading:15536149-Phosphorylation,
pubmed-meshheading:15536149-Protein-Serine-Threonine Kinases,
pubmed-meshheading:15536149-Proto-Oncogene Proteins,
pubmed-meshheading:15536149-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:15536149-RGS Proteins,
pubmed-meshheading:15536149-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:15536149-Repressor Proteins,
pubmed-meshheading:15536149-Tandem Repeat Sequences,
pubmed-meshheading:15536149-fms-Like Tyrosine Kinase 3
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pubmed:year |
2005
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pubmed:articleTitle |
RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.
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pubmed:affiliation |
Department of Medicine, Hematology, and Oncology, and the Interdisciplinary Clinical Research Center (IZKF), University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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