Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
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原发性渗出性淋巴瘤（PEL）是一种侵袭性的非霍奇金淋巴瘤，主要局限于体腔。卡波西肉瘤相关疱疹病毒是PEL的病原体。PEL是一种无法治愈的恶性肿瘤，用常规化疗治疗时预后极差。免疫调节药物（IMiD）来那度胺和泊马度胺是FDA批准的用于治疗各种疾病的药物。IMiD在其临床可达到的浓度内对大多数PEL细胞系显示出显著的抗增殖作用，通过将细胞阻滞在细胞周期的G 0/G1期，并且不诱导KSHV裂解周期再活化。尽管用来那度胺处理的PEL细胞的微阵列检查显示干扰素（IFN）信号传导的激活，但是阻断IFN途径并不阻断IMiD的抗PEL活性。IMiD的抗PEL作用涉及IRF 4的脑细胞依赖性抑制和IKZF 1的快速降解，但不涉及IKZF 3。小发夹RNA（shRNA）介导的MYC敲低增强了IMiD的细胞毒性。溴结构域和末端外结构域（BET）蛋白是表观遗传学的阅读器，其在染色质重塑和转录调控中起重要作用。BRD 4是一种广泛表达的转录辅激活因子，属于BET家族蛋白，已被证明与MYC相关的超级增强子共占据。开发了特异性BRD 4抑制剂，其在转录上抑制MYC。来那度胺与几种结构不同的BRD 4抑制剂（JQ-1、IBET 151和PFI-1）显示出协同细胞毒性。此外，与单独使用任一种药物相比，来那度胺和BRD 4抑制剂JQ-1的联合给药显著增加了原位异种移植模型中携带PEL的NOD.SCID小鼠的存活率。这些结果为IMiD单独使用和与BRD 4抑制剂联合使用治疗PEL的临床试验提供了令人信服的证据。
Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma localized predominantly in body cavities. Kaposi’s sarcoma-associated herpes virus is the causative agent of PEL. PEL is an incurable malignancy and has extremely poor prognosis when treated with conventional chemotherapy. Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are FDA approved drugs for the treatment of various ailments. IMiDs display pronounced anti-proliferative effect against majority of PEL cell lines within their clinically achievable concentrations, by arresting cells at G0/G1 phase of cell-cycle, and without any induction of KSHV lytic-cycle reactivation. Although microarray examination of PEL cells treated with lenalidomide revealed activation of interferon (IFN) signaling, blocking the IFN pathway did not block the anti-PEL activity of IMiDs. The anti-PEL effects of IMiDs involved cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1, but not IKZF3. Small hairpin-RNA (shRNA) mediated knockdown of MYC enhanced the cytotoxicity of IMiDs. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers which perform a vital role in chromatin remodeling and transcriptional regulation. BRD4, a widely expressed transcriptional coactivator, belongs to BET family of proteins, which has been shown to co-occupy the super-enhancers associated with MYC. Specific BRD4 inhibitors were developed which suppress MYC transcriptionally. Lenalidomide displayed synergistic cytotoxicity with several structurally distinct BRD4 inhibitors (JQ-1, IBET151, and PFI-1). Furthermore, combined administration of lenalidomide and BRD4 inhibitor JQ-1 significantly increased the survival of PEL bearing NOD.SCID mice in an orthotopic xenograft model as compared to either agent alone. These results provide compelling evidence for clinical testing of IMiDs alone and in combination with BRD4 inhibitors for PEL.
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DOI：
10.1084/jem.20031467
发表时间：
2004-04-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guasparri I;Keller SA;Cesarman E
通讯作者：
Cesarman E
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Arvanitakis, L;Mesri, EA;Cesarman, E
通讯作者：
Cesarman, E
影响因子：
20.3
作者：
Klein, U;Gloghini, A;Carbone, A
通讯作者：
Carbone, A
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi