| The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. | |
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MedLine Citation:
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PMID: 15774615 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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MLL (ALL-1) chimeric fusions and MLL partial tandem duplications (PTD) may have mechanistically distinct contributions to leukemogenesis. Acute myeloid leukemia (AML) blasts with the t(9;11)(p22; q23) express MLL-AF9 and MLL wild-type (WT) transcripts, while normal karyotype AML blasts with the MLL(PTD/WT) genotype express MLL PTD but not the MLL WT. Silencing of MLL WT in MLL(PTD/WT) blasts was reversed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and MLL WT induction was associated with selective sensitivity to cell death. Reduction of MLL PTD expression induced MLL WT and reduced blast colony-forming units, supporting opposing functions for MLL PTD and MLL WT whereby the MLL PTD contributes to the leukemic phenotype via a recessive gain-of-function. The coincident suppression of the MLL WT allele with the expression of the MLL PTD allele, along with the functional data presented here, supports the hypothesis that loss of WT MLL function via monoallelic repression contributes to the leukemic phenotype by the remaining mutant allele. These data from primary AML and the pharmacologic reversal of MLL WT silencing associated with a favorable alteration in the threshold for apoptosis suggest that these patients with poor prognosis may benefit from demethylating or histone deacetylase inhibitor therapy, or both. |
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Authors:
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Susan P Whitman; Shujun Liu; Tamara Vukosavljevic; Laura J Rush; Li Yu; Chunhui Liu; Marko I Klisovic; Kati Maharry; Martin Guimond; Matthew P Strout; Brian Becknell; Adrienne Dorrance; Rebecca B Klisovic; Christoph Plass; Clara D Bloomfield; Guido Marcucci; Michael A Caligiuri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2005-03-17 |
Journal Detail:
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Title: Blood Volume: 106 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2005 Jul |
Date Detail:
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Created Date: 2005-06-21 Completed Date: 2005-08-01 Revised Date: 2010-09-20 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 345-52 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine, Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Cell Death CpG Islands / genetics DNA Modification Methylases / antagonists & inhibitors* DNA-Binding Proteins / genetics* Down-Regulation Enzyme Inhibitors / pharmacology Gene Duplication* Gene Expression Regulation, Leukemic Genotype Histone Deacetylase Inhibitors* Humans Leukemia, Myeloid / drug therapy, genetics*, pathology Myeloid-Lymphoid Leukemia Protein Oligodeoxyribonucleotides Phenotype Proto-Oncogenes / genetics* Tandem Repeat Sequences Transcription Factors / genetics* Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA089317/CA/NCI NIH HHS; CA09338/CA/NCI NIH HHS; CA93548/CA/NCI NIH HHS; P30 CA16058/CA/NCI NIH HHS; R01 CA102031/CA/NCI NIH HHS; R01 CA89341/CA/NCI NIH HHS; U10 CA101140/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/MLL protein, human; 0/Oligodeoxyribonucleotides; 0/Transcription Factors; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; EC 2.1.1.-/DNA Modification Methylases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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