- Title
- Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia
- Creator
- Degryse, S.; De Bock, C. E.; Verrills, N. M.; Van Vlierberghe, P.; Cools, J.; Dun, M. D.; Demeyer, S.; Govaerts, I.; Bornschein, S.; Verbeke, D.; Jacobs, K.; Binos, S.; Skerrett-Byrne, D. A.; Murray, H. C.
- Relation
- Leukemia Vol. 32, Issue 3, p. 788-800
- Publisher Link
- http://dx.doi.org/10.1038/leu.2017.276
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2018
- Description
- Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens.
- Subject
- T-cell acute lymphoblastic leukemia (T-ALL); interleukin-7 receptor (IL7R); Janus kinase 3 (JAK3); phosphoproteomic profiling
- Identifier
- http://hdl.handle.net/1959.13/1409046
- Identifier
- uon:35928
- Identifier
- ISSN:0887-6924
- Rights
- This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
- Language
- eng
- Full Text
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