A new PML-RARs fusion transcript hints at the important role of PML dysregulation in the pathogenesis of APL.
A new PML-RARs fusion transcript hints at the important role of PML dysregulation in the pathogenesis of APL.
复制标题
一个新的 PML-RARs 融合转录本暗示了 PML 失调在 APL 发病机制中的重要作用。
DOI：
10.1080/10428190601186184
复制
发表时间：
2007
影响因子：
2.6
通讯作者：
Verma,Amit
中科院分区：
文献类型：
--
作者：
Opalinska,Joanna;Zhou,Li;Verma,Amit
Acute promyelocytic leukemia is associated with the 15: 17 chromosomal translocation, which results in the formation of a fusion PML-RARa oncoprotein. This oncoprotein blocks the transcription of retinoic acid regulated genes and leads to maturation arrest at promyelocytic stage of differentiation [1]. Multiple studies have now shown that the length of PML in the fusion protein can vary while the RARa portion remains constant and contains the DNA binding and ligand binding motifs (BF domains) of the retinoic acid receptor protein (Figure 1). Depending on the location of the breakpoint in the PML gene, 3 main types of fusion proteins have been described on the basis of their size [2]. The short (S) isoform is generated by fusion of PML exons 1 through 3 (encoding the RING, B boxes, and coiled-coil domain) to exon 3 of RARa. The longer (L) isoform contains exons 1 through 6 of PML and intermediate length variable (V) isoforms are formed after breakpoints around exon 6 of PML (Figure 1). Approximately 70% of APL patients express the L isoform, 20% the S isoform and the rest the V isoform. Even though these isoforms have differing sensitivities to ATRA, all respond to high doses given as a part of induction therapy. Other rare PML-RARa isoforms have also been noted that are formed because of alternative splicing of the PML transcripts. Interestingly each APL patient exhibits a unique isoform consistent with the clonal nature of this leukemia. In the study by Zayed et al.[3] the authors describe a new fusion PML-RARa transcript, which is formed by breakpoint between exons 5 and 6 in the PML gene. In contrast with the other known isoforms, this fusion oncoprotein leads to a frame shift in the RARa sequence, which then codes for a truncated version ofRARa. This predicted short version of protein will not have the Retinoic acid binding regions and thus theoretically would be resistant to ATRA therapy. This hypothesis is validated by the continued presence of Promyelocytic blasts after ATRA treatment in this report. Though this study describes a novel breakpoint, there are some questions raised by these findings. Even though the authors have studied the sequence of the fusion transcript at the RNA level, a determination of the exact breakpoint at the DNA level would have confirmed that this new RNA transcript is not formed as a result of alternative splicing. Additionally, the authors could not detect the transcript by RT-PCR at day 25 of treatment even in the presence of blasts in the marrow. Though RNA degradation could be a possibility, the authors do not comment if this conjecture was borne out by RT PCR studies of other housekeeping genes. The second explanation could be the rare possibility of a second leukemic clone (without the PML-RARa fusion protein) that could have become dominant after ATRA treatment. Cytogenetic examination performed at Day 25 would have been helpful in ruling out this rare possibility. A major point this paper illustrates is the importance of PML in the pathogenesis of APL. Since the fusion protein described by the authors encodes a very short fragment of the RARa protein, the presence of a dominant negative truncated PML is the most likely cause of this patient’s malignancy. PML is a protein that is involved in multiple pathways regulating cell proliferation, apoptosis, and aging [4]. Notably, PML participates in p53 dependent tumor suppressor pathways by regulating the acetylation and transcriptional activation of this
