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Zebrafish modeling of atypical PML-RARA isoform from acute promyelocytic leukemia patient and its implications for
Yin Ye1,2, Zonghan Zhao1,2, Wenjian Mo1,2
1Department of Hematology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China.
Abstract:
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.
Insights
A novel PML-RARA isoform (PA) was identified in acute promyelocytic leukemia (APL). A zebrafish model confirmed PA
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Acute promyelocytic leukemia (APL) is characterized by the PML-RARA fusion gene.
- Classical PML-RARA isoforms (L, V, S) are common, but atypical isoforms present prognostic challenges.
- A novel PA PML-RARA isoform was recently identified in an APL patient with unusual clinical features.
Purpose of the Study:
- To investigate the functional impact of the novel PA PML-RARA isoform.
- To evaluate the efficacy of all-trans retinoic acid (ATRA) treatment on the PA isoform using a zebrafish model.
- To provide insights for clinical management of APL with atypical PML-RARA isoforms.
Main Methods:
- Construction and utilization of a zebrafish model expressing the novel PA PML-RARA isoform.
- Comparative analysis of gene expression related to neutrophil development between PA and classical isoforms.
- Assessment of ATRA treatment response in the zebrafish model.
- Protein sequence and structure analysis of the PA isoform to evaluate ATRA binding site integrity.
Main Results:
- The PA PML-RARA isoform exhibited comparable effects on neutrophil-related gene expression to classical isoforms.
- ATRA treatment was effective in the PA PML-RARA zebrafish model.
- Structural analysis confirmed the PA isoform's similarity to classical ones and did not disrupt the ATRA binding site.
- The patient with the PA isoform achieved complete remission with ATRA and arsenic trioxide (ATO) treatment.
Conclusions:
- The novel PA PML-RARA isoform behaves similarly to classical isoforms regarding gene expression and ATRA response.
- The PML-RARA zebrafish model is a valuable tool for studying APL and predicting treatment efficacy.
- Protein structure prediction aids in understanding treatment mechanisms and supporting clinical strategies for APL.
