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PLZF and its fusion proteins are pomalidomide-dependent CRBN neosubstrates

ABSTRACT: Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related compounds and works as a Cullin Ring 4 E3 ubiquitin ligase (CRL4) with DDB1, CUL4, and ROC1. The substrate specificity of CRL4CRBN is modulated by thalidomide-related compounds. While lenalidomide is approved for the treatment of several diseases including multiple myeloma, 5q- syndrome, mantle cell lymphoma, and follicular lymphoma, pomalidomide is approved only for the treatment of lenalidomide-resistant multiple myeloma. Here we show that PLZF/ZBTB16 and its fusion proteins are pomalidomide-dependent neosubstrates of CRL4CRBN. PLZF joins to RARα or potentially other partner genes, and the translocation causes leukemias, such as acute promyelocytic leukemia and T-cell acute lymphoblastic leukemia. We demonstrate that pomalidomide treatment induces PLZF-RARα degradation, resulting in antiproliferation of leukemic cells expressing PLZF-RARα. This study highlights a potential therapeutic role of pomalidomide as a degrader of leukemogenic fusion proteins. Shimizu et al. identify PLZF/ZBTB16 and its fusion proteins as pomalidomide-dependent neosubstrates of the cereblon E3 ligase. The authors also report that pomalidomide induces their degradation and thereby exerts its anti-cancer effect in leukemic cells expressing the fusion proteins.

SUBMITTER: Shimizu N

PROVIDER: S-EPMC8586336 | biostudies-literature |

REPOSITORIES: biostudies-literature

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