RARA/PML Fusion Gene
APL, also known as acute myeloid leukemia-3, AML3, or M3 in the French-American-British (FAB) classification, is characterized by a predominance of malignant promyelocytes that carry a reciprocal translocation between the long arms of chromosomes 15 and 17: t(15;17)(q22;q11.2-q12).
This translocation is diagnostic for APL, as it is present in almost 100% of cases.
Borrow et al. (1990) used a NotI linking clone to detect this translocation on pulsed field gel electrophoresis and subsequently with conventional Southern analysis. The breakpoints in 10 APL cases examined were shown to cluster in a 12-kb region of chromosome 17, which contained 2 CpG-rich islands. A comparison of the sequence of cDNA clones from the region of the breakpoint was compared with the EMBL database revealed that the cDNA was that of RARA, which maps to 17q21.1, distal to the APL breakpoint region. They concluded that the cDNAs lay outside the 12-kb breakpoint region and that all of the 15q+ APL breakpoints lie in the first intron of RARA. Since RARA is interrupted in an intron, it is most likely that the product of the translocation is a fusion protein. Borrow et al. (1990) suggested that the chimeric fusion protein encoded by the 15q+ derivative would retain the DNA- and ligand-binding domains of RARA, whereas the transcription-activating function of the 5-prime end of RARA would be replaced with a novel N terminus, potentially changing the profile of genes activated. The involvement of RARA at the APL breakpoint may explain why the use of retinoic acid as a therapeutic differentiation agent in the treatment of acute myeloid leukemias is limited to APL. Lemons et al. (1990) also cloned the APL breakpoint region. Click this to see references in PubMed related to the ones listed in the paragraph above.
RAR and acute myeloid leukemia-1 (AML1; 151385) transcription factors are found in leukemias as fusion proteins with PML and ETO (CBFA2T1; 133435), respectively.
Association of PML-RAR and AML1-ETO with the NCOR-histone deacetylase complex is required to block hematopoietic differentiation.
Minucci et al. (2000) showed that PML-RAR and AML1-ETO exist in vivo within high molecular weight nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of NCOR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors.
Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results showed that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation. Click this to see references in PubMed related to the ones listed in the paragraph above.
