The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele.
The partial tandem duplication of MLL (MLL-PTD) 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 Mll-PTD in the absence of Mll-WT. These Mll(PTD/-) mice die at birth unlike the normal life expectancy of Mll(PTD/WT), Mll(WT/-), and Mll(WT/WT) mice. Using Mll(WT/WT) fetal liver cells (FLC) as baseline, we compared Mll(PTD/-) with Mll(PTD/WT) FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only Mll(PTD/WT) FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between Mll(PTD/WT) and Mll(PTD/-) mice suggest that the Mll-PTD mutation can up-regulate target genes in a dominant, gain-of-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the Mll-WT in the genesis of the observed abnormality.
Dorrance
Adrienne M
AM
Department of Internal Medicine, Division of Hematology and Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, USA.
Liu
Shujun
S
Chong
Anita
A
Pulley
Benjamin
B
Nemer
David
D
Guimond
Martin
M
Yuan
Weifeng
W
Chang
Dennis
D
Whitman
Susan P
SP
Marcucci
Guido
G
Caligiuri
Michael A
MA
D000483:Alleles; D000818:Animals; D005333:Fetus; D006412:Hematopoietic Stem Cells; D018398:Homeodomain Proteins / Q000235:genetics; D007938:Leukemia / Q000209:etiology; D008099:Liver / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D039904:Pluripotent Stem Cells; D020080:Tandem Repeat Sequences; D015854:Up-Regulation
D018398:Homeodomain Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein