Promyelocytic leukaemia gene

Borrow, J., Shipley, J, Howe, K, Kiely, F., Goddard, A., Sheer, D, Srivastava, A, Antony, A C., Fioretos, T, Mitelman, F., and Solomon, E. (1994) Molecular analysis of simple variant translocations in acute promyelocytic leukaemia Genes, Chromosomes Cancer 9, 234-243. 

Therefore, it appears that abnormal expressions of retinoic receptors may be involved in neoplastic progressions, and in some cases, these may completely hinder RA responsiveness. In other cases, as in remission of acute promyelocytic leukaemia, abnormal gene regulation by mutant RARs can be overcome by retinoic acid treatment. 

Zelent, A. (1994) Translocation of the RARa locus to the PML or PLZF gene in acute promyelocytic leukaemia. Br. J. Haem 86,451-460... 

Hioms, L R., Mm, T, Swansbury, G. J., Zelent, A., Dyer, M. J. S, and Catovsky, D (1994) Interstitial insertion of retinoic acid receptor-a gene in acute promyelocytic leukaemia with normal chromosomes 15 and 17 Blood 83,2946-2951... 

McKinney, C D, Golden, W. L., Gemma, N W, Swerdlow, S H, and Williams, M. E. (1994) RARA and PML gene rearrangements in acute promyelocytic leukaemia with complex translocations and atypical features Genes, Chromosomes Cancer 9,49-56... 

APL is most often associated with the t(15 17)(q22 q21) reciprocal chromosomal translocation which causes the fusion of the RARa locus with a gene of unknown function called PML (for promyelocytic leukaemia) and expression of PML-RARa chimeric proteins in all leukaemic cells [82-86]. Expression of the PML-RARa protein in transgenic mice results in development of APL which, as the human disease, can be induced into remission by ATRA treatment [87-90]. These results and studies with APL cells in vitro, or cells exogenously expressing PML-RARa, suggest that this oncoprotein is also a primary target of ATRA action [91, 92]. 

To date, three other APL-associated translocations of the RARa gene have been characterised at the molecular level. The t(5 17)(q35 q21) [96], t(ll 17)(q23 q21) [97, 98] and t(ll 17)(ql3 q21) [99] fuse RARa to Nucleophosmin (NPM), Promyelocytic Leukaemia Zinc Finger (PLZF), and Nuclear Mitotic Apparatus (NuMA) genes, respectively. These translocations result in the expression of chimeric RARa fusion proteins, which all retain the DNA and ligand binding domains of the receptor and gain a dimerization domain from the fusion partner (see Fig. 2 for a schematic representation). So far, the t(5 17)(q35 q21) and t(l I 17)(ql3 q21) have only been reported in index cases and, as with t(15 17)-associated APL, appeared to respond to treatment with ATRA [96,99]. In contrast, APL with t(l I 17)(q23 q21) has been reported on a recurrent basis, albeit at very low frequency, and has consistently been found unresponsive to ATRA therapy [100, 101]. 

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