Translational Therapeutics

Inhibition of the deubiquitinase USP10 induces degradation of SYK



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.

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Fig. 1: Small molecule inhibition of USP10 leads to degradation of SYK and targeted killing of activated SYK-driven cells.
Fig. 2: HBX19818 analogues have differential effects on SYK protein levels in Ba/F3-FLT3-ITD cells.
Fig. 3: USP10 and SYK physically associate and genetic knockdown or knockout of USP10 leads to SYK degradation.
Fig. 4: USP10 KD or small molecule inhibition leads to ubiquitination and degradation of SYK and increased total cellular ubiquitination.
Fig. 5: Loss of USP10 shortens the half-life of SYK protein with no effect on SYK mRNA transcription.
Fig. 6: Midostaurin potentiates the effects of USP10 inhibitors against Ba/F3-SYK-TEL cells.


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We thank Dr Nathanael Gray and Dr Richard Stone at Dana-Farber Cancer Institute—Harvard Medical School for valuable guidance on literature searches and critical revision of the manuscript.

Author information




J.Y., C.M. and E.W. conceptualised, designed and performed the studies. J.Y. and E.W. carried out data analyses and wrote the manuscript. A.C. assisted with the writing of the manuscript and preparation of figures. I.L. assisted with shRNA KD studies. R.M. helped design and provided important suggestions for His pulldown assay. S.A. provided important immunoblotting reagents. J.W. and N.G. provided FLT3 inhibitors. S.L. provided primary cells. R.S. provided valuable scientific feedback and guidance. M.S. provided valuable scientific feedback and guidance. S.B. conceptualised and designed the studies, carried out data analyses and wrote the manuscript. J.G. conceptualised and designed the studies.

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Correspondence to Sara Buhrlage or James D. Griffin.

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Prior to acquisition of normal PBMC samples, the subjects provided their informed consent to participate. Our studies were performed in accordance with the Declaration of Helsinki. IRB protocol number is 13-351 (consents 01-206 and 11-104 (which is now known as 17-000).

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The authors declare no competing interests.

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This study is supported by the National Institutes of Health research project grant (R01) CA211681.

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Yang, J., Meng, C., Weisberg, E. et al. Inhibition of the deubiquitinase USP10 induces degradation of SYK. Br J Cancer 122, 1175–1184 (2020).

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