PMID- 28852199 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20190208 LR - 20190215 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 32 IP - 3 DP - 2018 Mar TI - Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia. PG - 788-800 LID - 10.1038/leu.2017.276 [doi] AB - 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. FAU - Degryse, S AU - Degryse S AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - de Bock, C E AU - de Bock CE AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Demeyer, S AU - Demeyer S AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Govaerts, I AU - Govaerts I AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Bornschein, S AU - Bornschein S AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Verbeke, D AU - Verbeke D AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Jacobs, K AU - Jacobs K AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Binos, S AU - Binos S AD - Thermo Fisher Scientific, Scoresby, Victoria, Australia. FAU - Skerrett-Byrne, D A AU - Skerrett-Byrne DA AD - Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia. AD - Cancer Research Program, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, New South Wales, Australia. FAU - Murray, H C AU - Murray HC AD - Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia. AD - Cancer Research Program, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, New South Wales, Australia. FAU - Verrills, N M AU - Verrills NM AD - Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia. AD - Cancer Research Program, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, New South Wales, Australia. FAU - Van Vlierberghe, P AU - Van Vlierberghe P AUID- ORCID: 0000-0001-9063-7205 AD - Department of Pediatrics and Genetics, Center for Medical Genetics, Ghent University, Ghent, Belgium. AD - Cancer Research Institute Ghent, Ghent, Belgium. FAU - Cools, J AU - Cools J AD - VIB Center for Cancer Biology, Leuven, Belgium. AD - KU Leuven Center for Human Genetics, Leuven, Belgium. FAU - Dun, M D AU - Dun MD AD - Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia. AD - Cancer Research Program, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, New South Wales, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170830 PL - England TA - Leukemia JT - Leukemia JID - 8704895 EIN - Leukemia. 2018 Dec;32(12):2731. PMID: 30232463 PMC - PMC5843905 COIS- SB is an employee of Thermo Fisher Scientific, the corporation that produces Orbitrap mass spectrometers and proteomics software. SB is an LCMS applications specialist and provided technical support for MS methodology and data interpretation. Beyond this, the authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this manuscript. There are no patents, products in development, or marketed products to declare. All other authors declare no conflict of interest. EDAT- 2017/08/31 06:00 MHDA- 2017/08/31 06:01 PMCR- 2018/03/09 CRDT- 2017/08/31 06:00 PHST- 2017/03/30 00:00 [received] PHST- 2017/07/17 00:00 [revised] PHST- 2017/08/15 00:00 [accepted] PHST- 2017/08/31 06:00 [pubmed] PHST- 2017/08/31 06:01 [medline] PHST- 2017/08/31 06:00 [entrez] PHST- 2018/03/09 00:00 [pmc-release] AID - leu2017276 [pii] AID - 10.1038/leu.2017.276 [doi] PST - ppublish SO - Leukemia. 2018 Mar;32(3):788-800. doi: 10.1038/leu.2017.276. Epub 2017 Aug 30.