Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia
Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the PM...
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| Language: | English |
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0696 |
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| author | Pei-Han Yu Chen-Ying Zhu Yuan-Yuan Kang Hua Naranmandura Chang Yang |
| author_facet | Pei-Han Yu Chen-Ying Zhu Yuan-Yuan Kang Hua Naranmandura Chang Yang |
| author_sort | Pei-Han Yu |
| collection | DOAJ |
| description | Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the PML::RARα fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged PML allele rather than the PML::RARα fusion gene. Here, we report that mutations in the unrearranged PML allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged PML allele can confer ATO resistance through a protein–protein interaction. Therefore, the unrearranged PML allele should also be screened for drug-resistant mutations in relapsed APL patients. |
| format | Article |
| id | doaj-art-9ef740125a1f49d0a13b2a7272ef268c |
| institution | DOAJ |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-9ef740125a1f49d0a13b2a7272ef268c2025-08-20T03:11:48ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0696Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic LeukemiaPei-Han Yu0Chen-Ying Zhu1Yuan-Yuan Kang2Hua Naranmandura3Chang Yang4Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the PML::RARα fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged PML allele rather than the PML::RARα fusion gene. Here, we report that mutations in the unrearranged PML allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged PML allele can confer ATO resistance through a protein–protein interaction. Therefore, the unrearranged PML allele should also be screened for drug-resistant mutations in relapsed APL patients.https://spj.science.org/doi/10.34133/research.0696 |
| spellingShingle | Pei-Han Yu Chen-Ying Zhu Yuan-Yuan Kang Hua Naranmandura Chang Yang Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia Research |
| title | Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia |
| title_full | Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia |
| title_fullStr | Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia |
| title_full_unstemmed | Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia |
| title_short | Mutation in the Unrearranged PML Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia |
| title_sort | mutation in the unrearranged pml allele confers resistance to arsenic trioxide in acute promyelocytic leukemia |
| url | https://spj.science.org/doi/10.34133/research.0696 |
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