Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Br J Cancer. 2020 Apr;122(8):1175-1184. doi: 10.1038/s41416-020-0731-z. Epub 2020 Feb 4.
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.
越来越多的证据表明脾酪氨酸激酶（SYK）对于急性髓细胞白血病（AML）的转化和白血病克隆的维持至关重要。在 AML 患者中也发现其过表达，胎肝酪氨酸激酶 3（FLT3）发生激活突变，尤其是那些具有内部串联重复（FLT3-ITD）的患者，SYK 通过其转激活 FLT3-ITD 并对 FLT3 酪氨酸激酶抑制剂（TKI）的治疗产生耐药性。
我们之前描述了一种治疗 FLT3-ITD 阳性 AML 的药理学方法，该方法依赖于蛋白酶体介导的 FLT3 降解，通过抑制负责从 FLT3 上切割泛素的去泛素化酶（DUB）USP10。
在这里，我们表明 USP10 也是稳定 SYK 所必需的主要 DUB。我们进一步证明，USP10 靶向抑制剂可诱导 SYK 的降解。USP10 抑制导致活性 SYK 或致癌性 FLT3 驱动的细胞死亡，并增强这些细胞中 FLT3 抑制的抗白血病作用。
我们认为 USP10 抑制是抑制 SYK 的一种新方法，并阻碍其在 AML 病理中的作用，包括致癌性 FLT3 阳性 AML。此外，鉴于 SYK 在其他肿瘤中的显著转化作用，靶向 USP10 可能在癌症中有更广泛的应用。
