Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias

被引:155
作者
So, CW [1 ]
Lin, M [1 ]
Ayton, PM [1 ]
Chen, EH [1 ]
Cleary, ML [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA
关键词
ACUTE MYELOID-LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; RETINOIC ACID RECEPTOR; TRANSCRIPTION FACTORS; LEUCINE-ZIPPER; RAR-ALPHA; CHROMOSOMAL TRANSLOCATIONS; HISTONE METHYLTRANSFERASE; DROSOPHILA-TRITHORAX; HOMEOBOX GENES;
D O I
10.1016/S1535-6108(03)00188-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
MLL is a histone methyltransferase that can be converted into an oncoprotein by acquisition of transcriptional effector domains following heterologous protein fusions with a variety of nuclear transcription factors, cofactors, or chromatin remodeling proteins in acute leukemias. Here we demonstrate an alternative mechanism for activation of MLL following fusions with proteins (AF1p/Eps15 and GAS7)that normally reside in the cytoplasm. The coiled-coil oligomerization domains of these proteins are necessary and sufficient for leukemogenic transformation induced by the respective MLL fusion proteins. Furthermore, homodimerization of MLL by synthetic dimerization modules mimics bona fide MLL fusion proteins resulting in Hox gene activation and enhanced self-renewal of hematopoietic progenitors. Our studies support an oligomerization-dependent mechanism for oncogenic conversion of MLL, presumably in part by recruitment of accessory factors through the dimerized MLL moiety of the chimeric protein.
引用
收藏
页码:99 / 110
页数:12
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