TY - JOUR
T1 - The MLL partial tandem duplication
T2 - Differential, tissue-specific activity in the presence or absence of the wild-type allele
AU - Dorrance, Adrienne M.
AU - Liu, Shujun
AU - Chong, Anita
AU - Pulley, Benjamin
AU - Nemeir, David
AU - Guimond, Martin
AU - Yuan, Weifeng
AU - Chang, Dennis
AU - Whitman, Susan P.
AU - Marcucci, Guido
AU - Caligiuri, Michael A.
PY - 2008/9/15
Y1 - 2008/9/15
N2 - The partial tandem duplication of MLL (MLL-PJD) is found in 5% to 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in leukemic blasts is coincident with a silenced wild-type (WT) MLL allele. We therefore generated mice expressing the M//-PTD in the absence of M//-WT. These M//PTD/∼ mice die at birth unlike the normal life expectancy of M//PTD/WT, M//WT/-, and M//WT/WT mice. Using M//W1™T fetal liver cells (FLC) as baseline, we compared Mllp™- with M//PTD/WT FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only M//PTD'WT FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between M//PTD/WT and MIIPTD/- mice suggest that the M//-PTD mutation can upregulate target genes in a dominant, gainof-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the M/-WT in the genesis of the observed abnormality.
AB - The partial tandem duplication of MLL (MLL-PJD) is found in 5% to 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in leukemic blasts is coincident with a silenced wild-type (WT) MLL allele. We therefore generated mice expressing the M//-PTD in the absence of M//-WT. These M//PTD/∼ mice die at birth unlike the normal life expectancy of M//PTD/WT, M//WT/-, and M//WT/WT mice. Using M//W1™T fetal liver cells (FLC) as baseline, we compared Mllp™- with M//PTD/WT FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only M//PTD'WT FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between M//PTD/WT and MIIPTD/- mice suggest that the M//-PTD mutation can upregulate target genes in a dominant, gainof-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the M/-WT in the genesis of the observed abnormality.
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U2 - 10.1182/blood-2008-01-134338
DO - 10.1182/blood-2008-01-134338
M3 - Article
C2 - 18617636
AN - SCOPUS:55249114697
SN - 0006-4971
VL - 112
SP - 2508
EP - 2511
JO - Blood
JF - Blood
IS - 6
ER -