Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL.
Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL.
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发表时间：
1998
期刊：
影响因子：
30.8
通讯作者：
L. He;F. Guidez;C. Tribioli;D. Peruzzi;M. Ruthardt;A. Zelent;P. Pandolfi
中科院分区：
文献类型：
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作者：
L. He;F. Guidez;C. Tribioli;D. Peruzzi;M. Ruthardt;A. Zelent;P. Pandolfi
急性早幼粒细胞白血病(APL)与涉及维甲酸受体α基因(RARA)和PML基因的染色体易位相关，对维甲酸(RA)治疗敏感，而存在RARA和PLZF基因易位的APL患者对RA无效。我们已经建立了PML-RARA和PLZF-RARA转基因小鼠，并在这里表明，这些融合蛋白在APL的白血病发生和确定对RA的反应中发挥关键作用，因为PLZF-RARA转基因小鼠发生RA耐药白血病，而PML-RARA小鼠对RA治疗有反应。我们证明了PML-RARpha和PLZF-RARpha融合蛋白都可以作为转录抑制因子，并能够与核受体转录共抑制因子相互作用，例如SMRT。PLZF-RARpha，而不是PML-RARpha，可以通过其PLZF部分形成对RA不敏感的共阻遏复合体。组蛋白去乙酰酶抑制剂，如曲古抑素A(TSA)，与RA联合使用，可以克服PML-RARpha和PLZF-RARpha的转录抑制活性，以及表达PLZF-RARpha的白血病细胞对RA的无反应性。因此，我们的发现揭示了转录沉默在APL的发病机制和对RA的抵抗中所起的关键作用。
Acute promyelocytic leukaemia (APL), associated with chromosomal translocations involving the retinoic acid receptor alpha gene (RARA) and the PML gene, is sensitive to retinoic acid (RA) treatment, while APL patients harbouring translocations between RARA and the PLZF gene do not respond to RA. We have generated PML-RARA and PLZF-RARA transgenic mice and show here that these fusion proteins play a critical role in leukaemogenesis and in determining responses to RA in APL, because PLZF-RARA transgenic mice develop RA-resistant leukaemia, while PML-RARA mice are responsive to RA treatment. We demonstrate that both PML-RARalpha and PLZF-RARalpha fusion proteins can act as transcriptional repressors and are able to interact with nuclear receptor transcriptional co-repressors, such as SMRT. PLZF-RARalpha, but not PML-RARalpha, can form, via its PLZF moiety, co-repressor complexes which are insensitive to RA. Histone deacetylase inhibitors such as Trichostatin A (TSA), in combination with RA, can overcome the transcriptional repressor activity of PML-RARalpha and PLZF-RARalpha as well as the unresponsiveness of PLZF-RARalpha-expressing leukaemic cells to RA. Thus, our findings unravel a crucial role for transcriptional silencing in APL pathogenesis and resistance to RA in APL.