Inhibition of the deubiquitinase USP10 induces degradation of SYK.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
01
05
2019
accepted:
29
10
2019
pubmed:
6
2
2020
medline:
31
12
2020
entrez:
5
2
2020
Statut:
ppublish
Résumé
There is growing evidence that spleen tyrosine kinase (SYK) is critical for acute myeloid leukaemia (AML) transformation and maintenance of the leukemic clone in AML patients. It has also been found to be over-expressed in AML patients, with activating mutations in foetal liver tyrosine kinase 3 (FLT3), particularly those with internal tandem duplications (FLT3-ITD), where it transactivates FLT3-ITD and confers resistance to treatment with FLT3 tyrosine kinase inhibitors (TKIs). We have previously described a pharmacological approach to treating FLT3-ITD-positive AML that relies on proteasome-mediated FLT3 degradation via inhibition of USP10, the deubiquitinating enzyme (DUB) responsible for cleaving ubiquitin from FLT3. Here, we show that USP10 is also a major DUB required for stabilisation of SYK. We further demonstrate that degradation of SYK can be induced by USP10-targeting inhibitors. USP10 inhibition leads to death of cells driven by active SYK or oncogenic FLT3 and potentiates the anti-leukemic effects of FLT3 inhibition in these cells. We suggest that USP10 inhibition is a novel approach to inhibiting SYK and impeding its role in the pathology of AML, including oncogenic FLT3-positive AML. Also, given the significant transforming role SYK in other tumours, targeting USP10 may have broader applications in cancer.
Sections du résumé
BACKGROUND
There is growing evidence that spleen tyrosine kinase (SYK) is critical for acute myeloid leukaemia (AML) transformation and maintenance of the leukemic clone in AML patients. It has also been found to be over-expressed in AML patients, with activating mutations in foetal liver tyrosine kinase 3 (FLT3), particularly those with internal tandem duplications (FLT3-ITD), where it transactivates FLT3-ITD and confers resistance to treatment with FLT3 tyrosine kinase inhibitors (TKIs).
METHODS
We have previously described a pharmacological approach to treating FLT3-ITD-positive AML that relies on proteasome-mediated FLT3 degradation via inhibition of USP10, the deubiquitinating enzyme (DUB) responsible for cleaving ubiquitin from FLT3.
RESULTS
Here, we show that USP10 is also a major DUB required for stabilisation of SYK. We further demonstrate that degradation of SYK can be induced by USP10-targeting inhibitors. USP10 inhibition leads to death of cells driven by active SYK or oncogenic FLT3 and potentiates the anti-leukemic effects of FLT3 inhibition in these cells.
CONCLUSIONS
We suggest that USP10 inhibition is a novel approach to inhibiting SYK and impeding its role in the pathology of AML, including oncogenic FLT3-positive AML. Also, given the significant transforming role SYK in other tumours, targeting USP10 may have broader applications in cancer.
Identifiants
pubmed: 32015510
doi: 10.1038/s41416-020-0731-z
pii: 10.1038/s41416-020-0731-z
pmc: PMC7156412
doi:
Substances chimiques
USP10 protein, human
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
SYK protein, human
EC 2.7.10.2
Syk Kinase
EC 2.7.10.2
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1175-1184Subventions
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211681
Pays : United States
Références
Carnevale, J., Ross, L., Puissant, A., Banerji, V., Stone, R. M., DeAngelo, D. J. et al. SYK regulates mTOR signaling in AML. Leukemia 27, 2118–2128 (2013).
pubmed: 23535559
pmcid: 4028963
Dennehy, K. M., Ferwerda, G., Faro-Trindade, I., Pyz, E., Willment, J. A., Taylor, P. R. et al. Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. Eur. J. Immunol. 38, 500–506 (2008).
pubmed: 18200499
pmcid: 2430329
Rinaldi, A., Kwee, I., Taborelli, M., Largo, C., Uccella, S., Martin, V. et al. Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br. J. Haematol. 132, 303–316 (2006).
pubmed: 16409295
Chen, L., Monti, S., Juszczynski, P., Daley, J., Chen, W., Witzig, T. E. et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 111, 2230 (2008).
pubmed: 18006696
pmcid: 2234057
Buchner, M., Fuchs, S., Prinz, G., Pfeifer, D., Bartholomé, K., Burger, M. et al. Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res. 69, 5424 (2009).
pubmed: 19549911
Puissant, A., Fenouille, N., Alexe, G., Pikman, Y., Bassil, C. F., Mehta, S. et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25, 226–242 (2014).
pubmed: 24525236
pmcid: 4106711
Weisberg, E. L., Puissant, A., Stone, R., Sattler, M., Buhrlage, S. J., Yang, J. et al. Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase. Oncotarget 8, 52026–52044 (2017).
pubmed: 28881711
pmcid: 5581010
Nijman, S. M., Luna-Vargas, M. P., Velds, A., Brummelkamp, T. R., Dirac, A. M., Sixma, T. K. et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773–786 (2005).
pubmed: 16325574
Fraile, J. M., Quesada, V., Rodriguez, D., Freije, J. M. & Lopez-Otin, C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31, 2373–2388 (2012).
pubmed: 21996736
Jacq, X., Kemp, M., Martin, N. M. & Jackson, S. P. Deubiquitylating enzymes and DNA damage response pathways. Cell Biochem. Biophys. 67, 25–43 (2013).
pubmed: 23712866
pmcid: 3756857
Ristic, G., Tsou, W.-L. & Todi, S. V. An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes. Front. Mol. Neurosci. 7, 72–72 (2014).
pubmed: 25191222
pmcid: 4137239
Ebner, P., Versteeg, G. A. & Ikeda, F. Ubiquitin enzymes in the regulation of immune responses. Crit. Rev. Biochem Mol. Biol. 52, 425–460 (2017).
pubmed: 28524749
pmcid: 5490640
Mofers, A., Pellegrini, P., Linder, S. & D’Arcy, P. Proteasome-associated deubiquitinases and cancer. Cancer Metastasis Rev. 36, 635–653 (2017).
pubmed: 29134486
pmcid: 5721125
Sacco, J. J., Coulson, J. M., Clague, M. J. & Urbe, S. Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life 62, 140–157 (2010).
pubmed: 20073038
Katkere, B., Rosa, S. & Drake, J. R. The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. J. Biol. Chem. 287, 16636–16644 (2012). e-pub ahead of print 2012/03/28.
pubmed: 22451666
pmcid: 3351345
Mohapatra, B., Ahmad, G., Nadeau, S., Zutshi, N., An, W., Scheffe, S. et al. Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim. Biophys. Acta 1833, 122–139 (2013).
pubmed: 23085373
Taylor, S. J., Thien, C. B., Dagger, S. A., Duyvestyn, J. M., Grove, C. S., Lee, B. H. et al. Loss of c-Cbl E3 ubiquitin ligase activity enhances the development of myeloid leukemia in FLT3-ITD mutant mice. Exp. Hematol. 43, 191–206 e191 (2015).
pubmed: 25534201
Weisberg, E. L., Schauer, N. J., Yang, J., Lamberto, I., Doherty, L., Bhatt, S. et al. Inhibition of USP10 induces degradation of oncogenic FLT3. Nat. Chem. Biol. 13, 1207–1215 (2017).
pubmed: 28967922
pmcid: 6314479
Cools, J., Mentens, N., Furet, P., Fabbro, D., Clark, J. J., Griffin, J. D. et al. Prediction of resistance to small molecule FLT3 inhibitors. Cancer Res. 64, 6385 (2004).
pubmed: 15374944
Matsuo, Y., MacLeod, R. A., Uphoff, C. C., Drexler, H. G., Nishizaki, C., Katayama, Y. et al. Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). Leukemia 11, 1469–1477 (1997).
pubmed: 9305600
Weisberg, E., Boulton, C., Kelly, L. M., Manley, P., Fabbro, D., Meyer, T. et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1, 433–443 (2002).
pubmed: 12124173
Chou, T. C. & Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzym. Regul. 22, 27–55 (1984).
Reverdy, C., Conrath, S., Lopez, R., Planquette, C., Atmanene, C., Collura, V. et al. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chem. Biol. 19, 467–477 (2012).
pubmed: 22520753
Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G. S., Zhou, B., Carrasco, R. et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22, 345–358 (2012).
pubmed: 22975377
pmcid: 3478134
Paolini, R., Molfetta, R., Piccoli, M., Frati, L. & Santoni, A. Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement. Proc. Natl Acad. Sci. USA 98, 9611–9616 (2001).
pubmed: 11493682
Young, R. M., Hardy, I. R., Clarke, R. L., Lundy, N., Pine, P., Turner, B. C. et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood 113, 2508–2516 (2009).
pubmed: 18981293
pmcid: 2947310
Baudot, A. D., Jeandel, P. Y., Mouska, X., Maurer, U., Tartare-Deckert, S., Raynaud, S. D. et al. The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression. Oncogene 28, 3261 (2009).
Perova, T., Grandal, I., Nutter, L. M. J., Papp, E., Matei, I. R., Beyene, J. et al. Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 236ra262 (2014).
Uckun, F. M., Qazi, S., Cely, I., Sahin, K., Shahidzadeh, A., Ozercan, I. et al. Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia. Blood 121, 4348–4354 (2013).
pubmed: 23568490
pmcid: 3663427
Hahn, C. K., Berchuck, J. E., Ross, K. N., Kakoza, R. M., Clauser, K., Schinzel, A. C. et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 16, 281–294 (2009).
pubmed: 19800574
pmcid: 2803063
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1–pl1 (2013).
pubmed: 4160307
pmcid: 4160307
Kuno, Y., Abe, A., Emi, N., Iida, M., Yokozawa, T., Towatari, M. et al. Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 97, 1050 (2001).
pubmed: 11159536
Dierks, C., Adrian, F., Fisch, P., Ma, H., Maurer, H., Herchenbach, D. et al. The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. Cancer Res. 70, 6193 (2010).
pubmed: 20670954
Sargin, B., Choudhary, C., Crosetto, N., Schmidt, M. H. H., Grundler, R., Rensinghoff, M. et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110, 1004 (2007).
pubmed: 17446348
Fernandes, M. S., Reddy, M. M., Croteau, N. J., Walz, C., Weisbach, H., Podar, K. et al. Novel oncogenic mutations of CBL in human acute myeloid leukemia that activate growth and survival pathways depend on increased metabolism. J. Biol. Chem. 285, 32596–32605 (2010).
pubmed: 20622007
pmcid: 2952262
Abram, C. L. & Lowell, C. A. The expanding role for ITAM-based signaling pathways in immune cells. Sci. STKE 2007, re2 (2007).
pubmed: 17356173
Lu, J., Lin, W. H., Chen, S. Y., Longnecker, R., Tsai, S. C., Chen, C. L. et al. Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells. J. Biol. Chem. 281, 8806–8814 (2006).
pubmed: 16431925
Katz, E., Dubois-Marshall, S., Sims, A. H., Faratian, D., Li, J., Smith, E. S. et al. A gene on the HER2 amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of Syk. Br. J. Cancer 103, 401–410 (2010).
pubmed: 20628393
pmcid: 2920017
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N. et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 15, 489–500 (2009).
pubmed: 19477428
pmcid: 2743093
Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329–334 (2012).
pubmed: 22237022
pmcid: 3289956
Udyavar, A. R., Hoeksema, M. D., Clark, J. E., Zou, Y., Tang, Z., Li, Z. et al. Co-expression network analysis identifies Spleen Tyrosine Kinase (SYK) as a candidate oncogenic driver in a subset of small-cell lung cancer. BMC Syst. Biol. 7(Suppl 5), S1–S1 (2013).
pubmed: 24564859
pmcid: 4029366
Luangdilok, S., Box, C., Patterson, L., Court, W., Harrington, K., Pitkin, L. et al. Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res. 67, 7907 (2007).
pubmed: 17699797
Shin, G., Kang, T.-W., Yang, S., Baek, S.-J., Jeong, Y.-S. & Kim, S.-Y. GENT: gene expression database of normal and tumor tissues. Cancer Inform. 10, 149–157 (2011).