In vitro response to all-trans retinoic acid of acute promyelocytic leukemias with nonreciprocal PML/RARA or RARA/PML fusion genes

Acute promyelocytic leukemia (APL) is characterized by the t(15;17) cytogenetic abnormality leading to the expression of two fusion genes, PML/RARA and RARA/PML, and by its sensitivity to all-trans retinoic acid (ATRA) differentiating treatment. Rare APL cases lacking the t(15;17) have been described. We have previously reported two cases presenting with submicroscopic insertions of RARA or PML into chromosome 15 or 17, respectively. These insertions lead to the formation of potentially functional, nonreciprocal, PML/RARA or RARA/PML fusion genes, providing the unique opportunity to investigate in a human noncell-line model the respective role of PML/RARA or RARA/PML in retinoid signaling. Here, we report the in vitro response to ATRA of these two cases as well as of a third case presenting with submicroscopic insertion (15;17) and expressing exclusively PML/RARA, by morphological, functional, and immunological assays. The two cases expressing PML/RARA presented with an immunostaining pattern typical of APL and a positive response to ATRA, whereas the APL case expressing only a RARA/PML fusion transcript exhibited an immunostaining pattern typical of non-APL cells, and was resistant to ATRA. Our results confirm that sensitivity to ATRA requires expression of PML/RARA and strongly correlates with immunostaining, and demonstrate that expression of RARA/PML alone is sufficient for a cytological APL phenotype, but does not confer sensitivity to ATRA.