Abstract:
:JAK3 is a tyrosine kinase that associates with the common γ chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8(+) T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.
journal_name
Bloodjournal_title
Bloodauthors
Degryse S,de Bock CE,Cox L,Demeyer S,Gielen O,Mentens N,Jacobs K,Geerdens E,Gianfelici V,Hulselmans G,Fiers M,Aerts S,Meijerink JP,Tousseyn T,Cools Jdoi
10.1182/blood-2014-04-566687subject
Has Abstractpub_date
2014-11-13 00:00:00pages
3092-100issue
20eissn
0006-4971issn
1528-0020pii
blood-2014-04-566687journal_volume
124pub_type
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