Department of Chemical Biology, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan.
Commun Biol. 2021 Nov 11;4(1):1277. doi: 10.1038/s42003-021-02801-y.
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 CRL4 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 CRL4. 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.
泊马度胺和来那度胺是免疫调节剂，它们是从沙利度胺衍生而来的。 cereblon（CRBN）是沙利度胺和相关化合物的常见直接靶标，作为一个含有 DDB1、CUL4 和 ROC1 的 Cullin Ring 4 E3 泛素连接酶（CRL4）。CRL4 的底物特异性受沙利度胺相关化合物的调节。虽然来那度胺已被批准用于治疗多发性骨髓瘤、5q-综合征、套细胞淋巴瘤和滤泡性淋巴瘤等多种疾病，但泊马度胺仅被批准用于治疗来那度胺耐药的多发性骨髓瘤。在这里，我们表明 PLZF/ZBTB16 及其融合蛋白是 CRL4 的泊马度胺依赖性新底物。PLZF 与 RARα 或潜在的其他伙伴基因结合，易位导致白血病，如急性早幼粒细胞白血病和 T 细胞急性淋巴细胞白血病。我们证明泊马度胺治疗诱导 PLZF-RARα 的降解，导致表达 PLZF-RARα 的白血病细胞的增殖抑制。这项研究强调了泊马度胺作为一种潜在的治疗药物，可作为致白血病融合蛋白的降解剂。
