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Blood, 1 July 2005, Vol. 106, No. 1, pp. 345-352.
Prepublished online as a Blood First Edition Paper on March 17, 2005; DOI 10.1182/blood-2005-01-0204.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy
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, and
Michael A. Caligiuri
From the Department of Internal Medicine, Division of Hematology-Oncology, The Ohio State University, Columbus, OH; the Department of Veterinary Biosciences, The Ohio State University, Columbus, OH; the Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH; the Comprehensive Cancer Center of The Ohio State University, Columbus, OH; and the Cancer and Leukemia Group B, Durham, NC.
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 MLLPTD/WT genotype express MLL PTD but not the MLL WT. Silencing of MLL WT in MLLPTD/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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