2020
DOI: 10.1038/s41416-020-0731-z
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Inhibition of the deubiquitinase USP10 induces degradation of SYK

Abstract: 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). … Show more

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Cited by 20 publications
(20 citation statements)
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“…14 Yang et al provide compelling evidence that SYK can be degraded by inhibition of USP10 leading to cell death in AML cells driven by activated SYK or mutant FLT3. 1 The same group had shown previously that USP10 is also the major deubiquitinating enzyme for FLT3. 15 USP10 inhibition thus leads to dual degradation of FLT3 and SYK, which is beneficial; the combined inhibition of FLT3 and SYK by small molecules is more efficacious than inhibition with either an FLT3 or SYK inhibitor alone in AML.…”
Section: Mainmentioning
confidence: 88%
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“…14 Yang et al provide compelling evidence that SYK can be degraded by inhibition of USP10 leading to cell death in AML cells driven by activated SYK or mutant FLT3. 1 The same group had shown previously that USP10 is also the major deubiquitinating enzyme for FLT3. 15 USP10 inhibition thus leads to dual degradation of FLT3 and SYK, which is beneficial; the combined inhibition of FLT3 and SYK by small molecules is more efficacious than inhibition with either an FLT3 or SYK inhibitor alone in AML.…”
Section: Mainmentioning
confidence: 88%
“…6,7 Indeed, SYK has been reported to activate FLT3 through a direct interaction, a finding corroborated in the current study. 1,7 In support of these preclinical findings, two orally bioavailable SYK inhibitors, entospletinib and TAK-659, have been investigated in clinical trials in patients with AML alone and in combination with standard chemotherapy. Early responses have been reported, especially in patients with FLT3-mutated AML and high HOXA9/MEIS1 expression, such as MLL (mixed-lineage leukaemia)-rearranged and NPM1c (cytoplasmic nucleophosmin 1) mutant leukaemia.…”
Section: Mainmentioning
confidence: 98%
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