| Abrogation of MLL-AF10 and CALM-AF10 mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. | |
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MedLine Citation:
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PMID: 23138183 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL-AF10 and CALM-AF10 fusion oncoproteins respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here we demonstrate that MLL-AF10 and CALM-AF10 mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. Treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively suppressed proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemias bearing chromosomal translocations that involve the AF10 gene may benefit from small molecule therapeutics that inhibit H3K79 methylation.Leukemia accepted article preview online, 9 November 2012; doi:10.1038/leu.2012.327. |
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Authors:
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L Chen; A Deshpande; D Banka; K M Bernt; S Dias; C Buske; E J Olhava; S R Daigle; V M Richon; R M Pollock; S A Armstrong |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-09 |
Journal Detail:
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Title: Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K Volume: - ISSN: 1476-5551 ISO Abbreviation: Leukemia Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA [2] Department of Molecular and Cellular Biology, Harvard University. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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