JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model - PubMed (original) (raw)
. 2014 Nov 13;124(20):3092-100.
doi: 10.1182/blood-2014-04-566687. Epub 2014 Sep 5.
Charles E de Bock 1, Luk Cox 1, Sofie Demeyer 1, Olga Gielen 1, Nicole Mentens 1, Kris Jacobs 1, Ellen Geerdens 1, Valentina Gianfelici 2, Gert Hulselmans 3, Mark Fiers 1, Stein Aerts 3, Jules P Meijerink 4, Thomas Tousseyn 5, Jan Cools 1
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- PMID: 25193870
- DOI: 10.1182/blood-2014-04-566687
Free article
JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model
Sandrine Degryse et al. Blood. 2014.
Free article
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.
© 2014 by The American Society of Hematology.
Comment in
- HiJAKing T-ALL.
Asnafi V. Asnafi V. Blood. 2014 Nov 13;124(20):3038-40. doi: 10.1182/blood-2014-09-600627. Blood. 2014. PMID: 25395141
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