Schematic depiction of the key advance reported by Hussain et al in this issue of Blood. UCHL1 is a deubiquitinating enzyme that has been shown in previous work to promote malignant B-cell and plasma cell development (indicated by blue arrow pointing right) despite inhibiting mTORC1 (blue horizontal line with a short vertical “stop” line). The inhibition of mTORC1 has been enigmatic because the protein complex serves as a crucial positive regulator of cap-dependent mRNA translation and protein synthesis: a mandatory requirement for malignant growth. Hussain et al solved the enigma by demonstrating that UCHL1 promotes the assembly of the eIF4F translation initiation complex (red arrow pointing down), bypassing, thereby, the inhibitory impact of the UCHL1-mTORC1-4EBP1 axis on protein synthesis. Hussain et al also show that the enzymatic, deubiquitinating activity of UCHL1 is crucial for MYC-driven lymphoma in laboratory mice. This provided preclinical support for the contention that targeted inhibition of deubiquitination using small-molecule drugs may lead to new treatments for patients with lymphoma and myeloma.

Schematic depiction of the key advance reported by Hussain et al in this issue of Blood. UCHL1 is a deubiquitinating enzyme that has been shown in previous work to promote malignant B-cell and plasma cell development (indicated by blue arrow pointing right) despite inhibiting mTORC1 (blue horizontal line with a short vertical “stop” line). The inhibition of mTORC1 has been enigmatic because the protein complex serves as a crucial positive regulator of cap-dependent mRNA translation and protein synthesis: a mandatory requirement for malignant growth. Hussain et al solved the enigma by demonstrating that UCHL1 promotes the assembly of the eIF4F translation initiation complex (red arrow pointing down), bypassing, thereby, the inhibitory impact of the UCHL1-mTORC1-4EBP1 axis on protein synthesis. Hussain et al also show that the enzymatic, deubiquitinating activity of UCHL1 is crucial for MYC-driven lymphoma in laboratory mice. This provided preclinical support for the contention that targeted inhibition of deubiquitination using small-molecule drugs may lead to new treatments for patients with lymphoma and myeloma.

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