Promyelocytic leukemia protein

Promyelocytic leukemia protein (PML) (also known as MYL, RNF71, PP8675 or TRIM19) is the protein product of the PML gene. PML protein is a tumor suppressor protein required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the chromatin of the cell nucleus. These nuclear bodies are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in programmed cell death, genome stability, antiviral effects and controlling cell division. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers. PML was poorly understood until described in the findings of Grignani et al in their 1996 study of patients with acute promyelocytic leukemia (APL). It was found that the karyotype of 90% of APL patients included a reciprocal translocation, resulting in the fusion of the gene encoding retinoic acid receptor alpha, RARA, of chromosome 17 and the PML gene of chromosome 15, which had not previously been characterized. The resultant PML/RARalpha oncofusion gene was shown to disturb normal PML and RARalpha function, thus inhibiting the terminal differentiation of blood precursor cells and allowing the maintenance of a reserve of undifferentiated cells for cancerous progression. This implication of the PML gene in a pathological context led to a greater focus on the gene in future years. The PML gene is roughly 53 kilobase pairs in length and is located on the q arm of chromosome 15. It consists of 10 exons that are subject to shuffling through alternative splicing, yielding more than 15 known PML protein isoforms. While the isoforms vary at their C-terminal domain, they all contain a TRIpartite motif encoded by the first three exons of the gene. The TRIpartite motif consists of a zinc RING finger, two zinc binding domains, termed the B1 and B2 boxes, and an RBCC dimerization domain composed of two alpha helical coiled coil domains.