Murine isoforms of retinoic acid receptor gamma with specific patterns of expression.

We have characterized seven murine retinoic acid receptor gamma cDNA isoforms (mRAR-gamma 1 to -gamma 7) generated by alternative splicing of at least seven exons. These isoforms differ from one another in their 5' untranslated region and in two cases (mRAR-gamma 1 and -gamma 2) differ in their N-terminal A region, which is known to be important for differential transactivation by other nuclear receptors. mRAR-gamma 1 and -gamma 2, the predominant isoforms, are differentially expressed in adult tissues and during embryogenesis. Most notably, skin contains almost exclusively mRAR-gamma 1 transcripts. The conservation of the RAR-gamma isoforms from mouse to human together with their patterns of expression suggests that they perform specific functions, which may account for the pleiotropic effect of retinoic acid in embryogenesis and development

A case of AML characterized by a novel t(4;15)(q31;q22) translocation that confers a growth-stimulatory response to retinoid-based therapy

Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-transretinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving theTMEM154andRASGRF1genes. Analysis of primary cells from the patient revealed the expression ofTMEM154-RASGRF1mRNA and the resulting fusion protein, but no expression of the reciprocalRASGRF1-TMEM154fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML