Abstract
BackgroundThere 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).MethodsWe 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.ResultsHere, 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.ConclusionsWe 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.
Highlights
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
Given our recent finding that USP10 deubiquitinates mutant foetal liver tyrosine kinase 3 (FLT3),18 coupled with reported studies showing that FLT3 and SYK are interacting partners with each other and are targets of the same E3 ligase c-CBL,[6,7,15,16,17] we hypothesised that USP10 may play a role in stabilisation of SYK
Studies in our lab revealed wt SYK to be downregulated in FLT3-ITD-expressing Ba/F3 cells and MV4-11 cells in response to treatment with the deubiquitinating enzyme (DUB) inhibitors, HBX19818 and P22077, both of which inhibit the activity of USP7 as well as USP1018,23,24 (Fig. 1a, b)
Summary
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. 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. Inhibition of FLT3-ITD-expressing AML cells with FLT3 kinase inhibitors, such as midostaurin, quizartinib, gilteritinib, sorafenib or crenolanib, has been shown to be effective in clinical trials to induce and extend remissions; many patients become resistant to TKI treatment. Either knockdown of USP10 or pharmacologic inhibition of this DUB resulted in sustained loss of FLT3-ITD protein and induction of leukemic cell death. These results suggested that it might be possible to treat TKI-resistant patients with USP10 inhibitors, leading to suppression of kinase activity and cell death
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