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Comment
. 2021 Feb 4;137(5):584-586.
doi: 10.1182/blood.2020009827.

Targeting cereblon in AML

Steven Grant  1
Affiliations
Comment

Targeting cereblon in AML

Steven Grant. Blood. .
No abstract available

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Figures

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Schema of cereblon/CC-90009 interactions in the context of the UBS. Ubiquitin (Ub) is activated by a ubiquitin-activating enzyme (E1) and transferred to a ubiquitin-conjugating enzyme (E2) prior to linkage to protein substrates by a ubiquitin ligase (E3) complex, of which cereblon is a key component. The K48/K11 ubiquitination of substrates targets them for degradation by the 26S proteasome. CC-90009 promotes binding of cereblon to the translation termination protein GSPT1, which leads to the selective elimination of this protein. Loss of GSPT1 in AML cells triggers the ISR via ATF4, culminating in cell death. These events are opposed by loss of the alternative splicing modulators ILF2/ILF3, which diminish cereblon expression, as well as by hyperactivation of the mTOR pathway, which blocks GSPT1 degradation.
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