Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry
| Autor: | Sima Jeha, Takaya Moriyama, Hany Ariffin, Ting-Nien Lin, Shirley Kow Yin Kham, Yung-Li Yang, William E. Evans, Mary V. Relling, Wenjian Yang, Chengcheng Liu, Dong-Tsamn Lin, Chih-Hsiang Yu, Rina Nishii, Jun J. Yang, Ching-Hon Pui, Allen Eng Juh Yeoh |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nucleotide diphosphatase activity Immunology Biochemistry Germline 03 medical and health sciences 0302 clinical medicine Acute lymphocytic leukemia medicine Genetics Thiopurine methyltransferase biology business.industry Cell Biology Hematology medicine.disease Mercaptopurine Haematopoiesis 030104 developmental biology 030220 oncology & carcinogenesis Toxicity biology.protein business Pharmacogenetics medicine.drug |
| Zdroj: | Blood. 130:1209-1212 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-05-782383 |
| Popis: | Prolonged exposure to thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg, TPMT). Recently, our group and others identified germ line genetic variants in NUDT15 as another major cause of thiopurine-related myelosuppression, particularly in Asian and Hispanic people. In this article, we describe 3 novel NUDT15 coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with ALL enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children's Research Hospital. Patients carrying these variants experienced significant toxicity and reduced tolerance to MP across treatment protocols. Functionally, all 3 variants led to partial to complete loss of NUDT15 nucleotide diphosphatase activity and negatively influenced protein stability. In particular, the p.G17_V18del variant protein showed extremely low thermostability and was completely void of catalytic activity, thus likely to confer a high risk of thiopurine intolerance. This in-frame deletion was only seen in African and European patients, and is the first NUDT15 risk variant identified in non-Asian, non-Hispanic populations. In conclusion, we discovered 3 novel loss-of-function variants in NUDT15 associated with MP toxicity, enabling more comprehensive pharmacogenetics-based thiopurine dose adjustments across diverse populations. |
| Databáze: | OpenAIRE |
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