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Mutant JAK3 signaling is increased by loss of wild-type JAK3 or by acquisition of secondary JAK3 mutations in T-ALL

Lookup NU author(s): Professor Christine Harrison FRCPath FMedSci, Dr Simona Constantinescu

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Abstract

© 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.


Publication metadata

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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