The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia

被引:185
作者
Vangala, RK
Heiss-Neumann, MS
Rangatia, JS
Singh, SM
Schoch, C
Tenen, DG
Hiddemann, W
Behre, G
机构
[1] Univ Munich, Dept Internal Med 3, Hosp Grosshadern, D-81377 Munich, Germany
[2] GSF Munich, Natl Res Ctr Environm & Hlth, Munich, Germany
[3] Harvard Univ, Sch Med, Inst Med, Boston, MA USA
关键词
D O I
10.1182/blood-2002-04-1288
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The transcription factor PU.1 plays a pivotal role in normal myeloid differentiation. PU.1(-/-) mice exhibit a complete block in myeloid differentiation. Heterozygous PU.1 mutations were reported In some patients with acute myeloid leukemia (AML), but not in AML with translocation t(8;21), which gives rise to the fusion gene AML1-ETO. Here we report a negative functional impact of AML1-ETO on the transcriptional activity of PU.1.AML1-ETO physically binds to PU.1 in t(8;21)(+) Kasumi-1 cells. AML1-ETO binds to the beta(3)beta(4) region in the DNA-binding domain of PU.1 and displaces the coactivator c-Jun from PU.1, thus down-regulating the transcriptional activity of PU.1. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA-binding capacity of PU.1 AML1-ETO down-regulates the transactivation capacity of PU.1 in myeloid U937 cells, and the expression levels of PU.1 target genes in AML French-American-British (FAB) subtype M2 patients with t(8;21) were lower than in patients without t(8;21). Conditional expression of AML1-ETO causes proliferation in mouse bone marrow cells and inhibits antiproliferative function of PU.1. Overexpression of PU.1, however, differentiates AML1-ETO-expressing Kasumi-1 cells to the monocytic lineage. Thus, the function of PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation. (C) 2003 by The American Society of Hematology.
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页码:270 / 277
页数:8
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