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Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia
M Alcalay1, D Zangrilli, M Fagioli
1Istituto Clinica Medica I, University of Perugia, Policlinico Monteluce, Italy.
Abstract:
Two chimeric genes, PML-RAR alpha and RAR alpha-PML, are formed as a consequence of the acute promyelocytic leukemia (APL)-specific reciprocal translocation of chromosomes 15 and 17 [t(15;17)]. PML-RAR alpha is expressed as a fusion protein. We investigated the organization and expression pattern of the RAR alpha-PML gene in a series of APL patients representative of the molecular heterogeneity of the t(15;17) and found (i) two types of RAR alpha-PML mRNA junctions (RAR alpha exon 2/PML exon 4 or RAR alpha exon 2/PML exon 7) that maintain the RAR alpha and PML longest open reading frames aligned and are the result of chromosome 15 breaking at two different sites; and (ii) 10 different RAR alpha-PML fusion transcripts that differ for the assembly of their PML coding exons. A RAR alpha-PML transcript was present in most, but not all, APL patients.
Insights
Acute promyelocytic leukemia (APL) involves chimeric genes like PML-RAR alpha. This study details the diverse organization and expression of the RAR alpha-PML gene in APL patients, revealing varied mRNA junctions and fusion transcripts.
Area of Science:
- Molecular Biology
- Hematology
- Genetics
Background:
- Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translocation, t(15;17).
- This translocation results in the formation of chimeric genes, primarily PML-RAR alpha, which is a known fusion protein in APL.
- The reciprocal RAR alpha-PML gene is also formed, but its organization and expression patterns are less understood.
Purpose of the Study:
- To investigate the molecular organization and expression patterns of the RAR alpha-PML gene in APL patients.
- To characterize the heterogeneity of RAR alpha-PML transcripts associated with the t(15;17) translocation.
- To identify different mRNA junctions and fusion transcript variants.
Main Methods:
- Analysis of RAR alpha-PML gene organization and expression in a series of APL patients.
- Identification and characterization of different RAR alpha-PML mRNA junctions.
- Sequencing and analysis of fusion transcripts to determine the assembly of PML coding exons.
Main Results:
- Two distinct RAR alpha-PML mRNA junctions were identified: RAR alpha exon 2/PML exon 4 and RAR alpha exon 2/PML exon 7.
- These junctions result from breaks at different sites on chromosome 15, maintaining open reading frames.
- Ten different RAR alpha-PML fusion transcripts were found, varying in the assembly of PML coding exons.
- A RAR alpha-PML transcript was detected in most, but not all, APL patients studied.
Conclusions:
- The RAR alpha-PML gene exhibits significant molecular heterogeneity in APL patients with the t(15;17) translocation.
- Variations in mRNA junctions and fusion transcript assembly contribute to the molecular landscape of APL.
- Understanding this heterogeneity is crucial for comprehending APL pathogenesis and potentially for targeted therapies.
