Zebrafish modeling of atypical PML-RARA isoform from acute promyelocytic leukemia patient and its implications for clinical treatment.

Acute promyelocytic leukemia (APL) is driven by the specific fusion gene PML-RARA produced by chromosomal translocation. Three classic isoforms, L, V, and S, are found in more than 95% of APL patients. However, atypical PML-RARA isoforms are usually associated with uncertain disease progression and treatment prognosis. Recently, we found a novel PML-RARA isoform (named PA) in a patient with atypical clinical characteristics of APL. In order to provide valuable insights for clinical treatment, we constructed the novel PML-RARA isoform zebrafish model for all-trans retinoic acid (ATRA) treatment experiments and comparison with classical isoforms. We found that the effect of PA PML-RARA on the expression of neutrophil-related genes was comparable with classical isoforms and ATRA treatment worked successfully in the zebrafish model. Sequence and structure analysis of the PA protein confirmed its similarity to classical isoforms and the fusion site of PA PML-RARA did not affect the ATRA binding site. As expected, the patient achieved complete remission within two months of treatment with ATRA in combination with arsenic trioxide (ATO) and had a favorable prognosis during the three-year follow-up. Our study highlights the accuracy and efficacy of the PML-RARA zebrafish model in combination with protein structure prediction in support of clinical treatment strategies.