Chen Z, Guidez F, Rousselot P, Agadir A, Chen S J, Wang Z Y, Degos L, Zelent A, Waxman S, Chomienne C
Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Laboratory of Shanghai Second Medical University, Rui-Jin Hospital, China.
Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1178-82. doi: 10.1073/pnas.91.3.1178.
Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL.
最近，我们描述了急性早幼粒细胞白血病（APL）中一种复发性变异易位，即t(11;17)(q23;q21)，它使编码锌指蛋白的基因PLZF与编码维甲酸受体α（RARα）的RARA并列。我们现已克隆了编码PLZF-RARα嵌合蛋白的cDNA，并研究了它们的反式激活活性。在瞬时表达试验中，PLZF(A)-RARα和PLZF(B)-RARα融合蛋白，就像APL中著名的t(15;17)易位产生的PML-RARα蛋白一样，在维甲酸存在的情况下拮抗内源性和转染的野生型RARα。共转染试验表明，即使使用极低浓度的表达PLZF-RARα的质粒，也能显著抑制RARα的反式激活活性。当PLZF-RARα融合蛋白与表达RARα和维甲酸X受体α（RXRα）的载体共转染时，观察到“显性负”效应。在对维甲酸敏感的髓系细胞中观察到的这些异常反式激活特性强烈提示PLZF-RARα融合蛋白参与了APL的分子发病机制。
