Sirulnik Andres, Melnick Ari, Zelent Arthur, Licht Jonathan D
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, NY 10029, USA.
Best Pract Res Clin Haematol. 2003 Sep;16(3):387-408. doi: 10.1016/s1521-6926(03)00062-8.
It has been 12 years since the simultaneous discovery of the unique sensitivity of acute promyelocytic leukaemia (APL) to differentiation therapy with all-trans retinoic acid (ATRA) and the discovery that the retinoic acid receptor alpha (RARalpha) gene was rearranged in APL. Nearly 98% of cases of APL are associated with t(15;17) chromosomal translocation and fusion of the PML gene to that encoding RARalpha to yield an abnormal receptor with the capability of de-regulating gene expression in the haematopoietic cell, causing differentiation block and eventually the development of leukaemia. Since this original discovery, four other translocations were described in APL. In each of these the RARalpha gene is fused to different partner genes, all yielding aberrant nuclear receptors. These fusion proteins share in common the ability to repress rather than activate retinoic acid targets, one so strongly that the result is an ATRA-resistant form of the disease. In addition each of the partner proteins is important for normal cell growth and development. In this chapter we explore the biology of the RARalpha, the fusion proteins created in APL and the normal forms of the partner proteins. Through continued study of this disease it is hoped that novel treatments, potentially more applicable to other forms of leukaemia, may arise.
自同时发现急性早幼粒细胞白血病（APL）对全反式维甲酸（ATRA）分化疗法具有独特敏感性以及维甲酸受体α（RARα）基因在APL中发生重排以来，已经过去了12年。近98%的APL病例与t(15;17)染色体易位以及PML基因与编码RARα的基因融合有关，从而产生一种异常受体，该受体能够失调造血细胞中的基因表达，导致分化阻滞并最终引发白血病。自最初发现以来，在APL中又描述了其他四种易位。在每一种情况中，RARα基因都与不同的伙伴基因融合，均产生异常核受体。这些融合蛋白的共同特点是能够抑制而非激活维甲酸靶标，其中一种抑制作用非常强烈，导致出现对ATRA耐药的疾病形式。此外，每种伙伴蛋白对正常细胞生长和发育都很重要。在本章中，我们将探讨RARα的生物学特性、APL中产生的融合蛋白以及伙伴蛋白的正常形式。通过对这种疾病的持续研究，有望开发出可能更适用于其他白血病形式的新疗法。
