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Lookup NU author(s): Professor Christine Harrison FRCPath FMedSci, Dr Simona Constantinescu
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© 2018 by The American Society of Hematology. The Janus kinase 3 (JAK3) tyrosine kinase is mutated in 10% to 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases. JAK3 mutants induce constitutive JAK/STAT signaling and cause leukemia when expressed in the bone marrow cells of mice. Surprisingly, we observed that one third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of which are monoallelic and others that are biallelic. Our data suggest that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to the common γ chain and thereby suppresses its oncogenic potential. We demonstrate that JAK3 (M511I) can increase its limited oncogenic potential through the acquisition of an additional mutation in the mutant JAK3 allele. These double JAK3 mutants show increased STAT5 activation and increased potential to transform primary mouse pro-T cells to interleukin-7-independent growth and were not affected by wild-type JAK3 expression. These data extend our insight into the oncogenic properties of JAK3 mutations and provide an explanation of why progression of JAK3-mutant T-ALL cases can be associated with the accumulation of additional JAK3 mutations.
Author(s): Degryse S, Bornschein S, De Bock CE, Leroy E, Bempt MV, Demeyer S, Jacobs K, Geerdens E, Gielen O, Soulier J, Harrison CJ, Constantinescu SN, Cools J
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2018
Volume: 131
Issue: 4
Pages: 421-425
Online publication date: 25/01/2018
Acceptance date: 23/11/2017
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/blood-2017-07-797597
DOI: 10.1182/blood-2017-07-797597
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