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POSTER NO: 419 Genomic Sequence of RARa Gene: Implication of Intron 2 Sequence in the t(15;17) Translocation and Formation of Variant-type PML-RARa Fusion Transcript in Acute Promyelocytic Leukemia
Bai-Wei Gu The physiologic actions of retinoic acids (RAs) are mediated through retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARa gene has drawn particular attention because it is the common target in all chromosomal translocations in acute promyelocytic leukemia (APL), a unique model in cancer research which responds to the differentiation inducer all-trans-retinoic acid (ATRA). In the great majority of APL patients, RARa gene, normally situated on 17q21, is fused to PML gene on 15q22 as a result of the t (15;17) translocation. Three distinct types of PML-RARa transcripts, the long (L)-type, the short (S)-type and the variant (V)-type, have been identified in different patients, while the precise mechanisms underlying the V-type transcript remained unclear. To get further insights into the molecular basis of the t(15;17) and resultant fusion gene transcripts, we sequenced the entire genomic DNA region of RARa gene contained in a BAC clone. Comparison of the exon-intron organization of RARs and RXRs has provided information to understand the evolution of this multiple gene family. Intron 2 sequence is closely related to APL molecular pathology at genomic level, since it harbors all 17q21 breakpoints and consensus motifs with loop structure were identified at the hotspots of the breakpoints. Moreover, all previously reported sequences inserted into PML-RARa taking part in V-type transcripts were found in this intron, most of them being flanked by gt splice donor sites. Therefore, fusion of truncated PML exon 6 to these 'cryptic' coding sequences maintains the open reading frame (ORF) of the chimeric transcript. |