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RAR alpha1/RAR alpha2-PML mRNA expression in acute promyelocytic leukemia cells: a molecular and laboratory-clinical
1Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY 10467, USA.
Abstract:
In addition to the major fusion gene PML-RAR alpha, the t(15; 17) in acute promyelocytic leukemia (APL) produces the reciprocal fusion gene RAR alpha-PML. To determine the scope of RAR alpha-containing mRNA expression in APL cells, we tested PML-RAR alpha-positive APL cells for the presence of mRNAs initiated from two distinct RAR alpha gene promoters, alpha1 and alpha2. From the normal allele, both RAR alpha1 and RAR alpha2 mRNAs were expressed in all APL cases (N = 24). From the translocated allele, RAR alpha1-PML mRNA was expressed in 77% and RAR alpha2-PML mRNA in 28% of cases (N = 98). RAR alpha2-PML mRNA was not observed in the absence of RAR alpha1-PML mRNA. There was no association between RAR alpha1-PML or RAR alpha2-PML mRNA expression and the type of PML-RAR alpha mRNA formed by either 5' or 3' breaksites in the PML gene. RAR alpha1-PML mRNAs and RAR alpha2-PML mRNAs from 5' PML breaksite cases coded for full-length RAR alpha-PML proteins but RAR alpha2-PML mRNAs from 3' PML breaksite cases encoded a truncated RAR alpha2 peptide. RAR alpha1/alpha2-PML mRNA expression was not associated with differences in APL cell sensitivity to all-trans retinoic acid(tRA)-induced differentiation in vitro or in clinical outcome after tRA or chemotherapy induction therapy (protocol E2491). Our analysis indicated that RAR alpha1/alpha2-PML mRNA expression markedly differs from normal RAR alpha1/alpha2 mRNA expression, that the difference in RAR alpha1-PML and RAR alpha2-PML mRNA expression frequency is primarily related to the genomic separation of the RAR alpha1 and RAR alpha2 coding exons, and that variations in RAR alpha1/alpha2-PML mRNA expression likely have no clinically relevant function in APL cells.
Insights
The reciprocal fusion gene RAR alpha-PML in acute promyelocytic leukemia (APL) shows varied mRNA expression from its promoters. This expression difference, linked to gene structure, does not impact APL cell sensitivity to retinoic acid or clinical outcomes.
Area of Science:
- Molecular Biology
- Hematology
- Cancer Genetics
Background:
- Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation, creating the PML-RAR alpha fusion gene.
- This translocation also produces a reciprocal RAR alpha-PML fusion gene, whose expression in APL cells is not fully understood.
Purpose of the Study:
- To investigate the expression patterns of RAR alpha-PML fusion transcripts originating from the alpha1 and alpha2 promoters in APL cells.
- To determine if RAR alpha-PML mRNA expression correlates with clinical features or treatment response in APL patients.
Main Methods:
- Analysis of RAR alpha-PML mRNA expression using quantitative methods in a cohort of APL patients.
- Correlation of mRNA expression levels with PML gene break sites, protein product, and clinical data, including response to all-trans retinoic acid (tRA).
Main Results:
- Both RAR alpha1 and RAR alpha2 mRNAs were expressed from the normal allele in all APL cases.
- RAR alpha1-PML mRNA was detected in 77% of cases, while RAR alpha2-PML mRNA was found in 28%, with RAR alpha2-PML expression dependent on RAR alpha1-PML.
- RAR alpha1/alpha2-PML mRNA expression did not correlate with PML break site, protein truncation, tRA sensitivity, or clinical outcome.
Conclusions:
- RAR alpha1/alpha2-PML mRNA expression patterns differ significantly from normal RAR alpha1/alpha2 mRNA expression.
- The frequency of RAR alpha1-PML and RAR alpha2-PML mRNA expression is influenced by the genomic arrangement of RAR alpha gene promoters.
- Variations in RAR alpha1/alpha2-PML mRNA expression appear to have no significant clinical relevance in APL patients treated with tRA or chemotherapy.