Title: JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model
Authors: Degryse, Sandrine
de Bock, Charles E
Cox, Luk
Demeyer, Sofie
Gielen, Olga
Mentens, Nicole
Jacobs, Kris
Geerdens, Ellen
Gianfelici, Valentina
Hulselmans, Gert
Fiers, Mark
Aerts, Stein
Meijerink, Jules P
Tousseyn, Thomas
Cools, Jan # ×
Issue Date: Nov-2014
Publisher: W.B. Saunders
Series Title: Blood vol:124 issue:20 pages:3092-100
Article number: 10.1182/blood-2014-04-566687
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.
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Molecular Biology of Leukemia
Translational Cell & Tissue Research
× corresponding author
# (joint) last author

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