TY - JOUR
T1 - The MLL partial tandem duplication
T2 - Evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy
AU - Whitman, Susan P.
AU - Liu, Shujun
AU - Vukosavljevic, Tamara
AU - Rush, Laura J.
AU - Yu, Li
AU - Liu, Chunhui
AU - Klisovic, Marko I.
AU - Maharry, Kati
AU - Guimond, Martin
AU - Strout, Matthew P.
AU - Becknell, Brian
AU - Dorrance, Adrienne
AU - Klisovic, Rebecca B.
AU - Plass, Christoph
AU - Bloomfield, Clara D.
AU - Marcucci, Guido
AU - Caligiuri, Michael A.
PY - 2005/7/1
Y1 - 2005/7/1
N2 - 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 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.
AB - 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 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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U2 - 10.1182/blood-2005-01-0204
DO - 10.1182/blood-2005-01-0204
M3 - Article
C2 - 15774615
AN - SCOPUS:22044452929
SN - 0006-4971
VL - 106
SP - 345
EP - 352
JO - Blood
JF - Blood
IS - 1
ER -