Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy

项目总结 间变性大细胞淋巴瘤(ALCL)由一组成熟的T细胞肿瘤组成，这些肿瘤 CD30的表达与间变性细胞学ALCL亚型根据其状态分为两类 间变性淋巴瘤激酶(ALK)、ALK+和ALK-。而AlK+AlCL相对均一，AlK-AlCL 代表由全身性ALK阴性和原发皮肤ALCL(PC-ALCL)组成的异质性组。 新近发现的乳房种植相关(BIA)ALCL，它发生在周围的浆液瘤空腔中 乳房植入物，被认为是一种独特的临床和病理实体，具有相同的形态特征 用ALK-ALCL。目前ALCL的治疗策略主要基于侵袭性B细胞淋巴瘤 养生法。然而，ALK-ALCL患者的预后通常比ALK+患者差得多 ALCL。因此，需要开发新的、最好是基于小分子的靶向疗法来治疗这些疾病 淋巴系统恶性肿瘤，尤其是ALK和BIA ALCL病例。实现这一目标的一个主要障碍是缺乏 系统而全面地理解ALK-和BIA-AlCL的深层分子特征 病理学，这显然是必要的，以确定关键的治疗脆弱性。解决以下方面的差距 我们在ALCL中应用了无偏高通量CRISPR筛查，并发现了意想不到的 IL-1R-MyD88通路在支持ALK-和BIA-ALCL中的作用IL-1R信号通路是关键 免疫和炎症的中介物，已被证明在许多实体肿瘤中发挥关键作用；然而， 它在淋巴系统恶性肿瘤中的作用尚未确定。事实上，我们的初步研究提供了第一个 明确的证据表明，IL-1R1通路在支持ALK-和BIA ALCL细胞存活中起着重要作用。 临床上，我们发现IL-1受体和IL-1α的表达在原发性ALK患者中持续升高，并且 这与初级样本中IL-1R信号激活(p-IRAK4水平)相关。此外，使用rna-seq 分析发现，在ALK-ALCL中存在一组IL-1R途径调控基因，它们与 反映JAK-STAT3活性和TH17/TH1表型的特征。最后，一种高度特异的IRAK4抑制剂 在体外和小鼠异种移植模型中显示出良好的抗ALK-和BIA-ALCL活性。总而言之，这些 研究结果有力地支持了我们的假设，即IL-1R途径促进ALK-和BIA-ALCL 而靶向该通路可能成为治疗这些疾病的一种新策略。在这 研究中，我们将通过以下目的来验证我们的假设：1)阐明IL-1R途径在 ALK-和BIA-ALCL，2)对该通路调节机制的理解及其与复发的关系 ALCL中的遗传损害，以及3)IL-1R通路作为这些疾病的新治疗靶点的有效性 恶性肿瘤。拟议中的研究应该为推动这些的分子电路提供关键的见解。 各种类型的ALCL，并因此导致针对这些疾病的新的靶向治疗策略的开发 明显的淋巴增生性疾病。

PROJECT SUMMARY Anaplastic large cell lymphoma (ALCL) comprises a collection of mature T-cell neoplasms that share elevated expression of CD30 and anaplastic cytology. ALCL subtypes are divided into two classes based on the status of anaplastic lymphoma kinase (ALK), ALK+ and ALK-. While ALK+ ALCL is relatively homogeneous, ALK- ALCL represents a heterogeneous group comprising systemic ALK negative and primary cutaneous ALCL (pC-ALCL). The recently recognized breast implant-associated (BIA) ALCL, which arises in the seroma cavity surrounding breast implants, was acknowledged as a distinct clinical and pathological entity that shares morphologic features with ALK- ALCL. Current therapeutic strategies for ALCL are largely based on aggressive B-cell lymphoma regimens. However, the outcomes are generally much worse in patients with ALK- ALCL than in those with ALK+ ALCL. Thus, there is a need to develop novel, preferably small molecule-based targeted therapies for these lymphoid malignancies, especially in ALK- and BIA ALCL cases. A major barrier to this goal is the lack of a systematic and comprehensive understanding of the deep molecular characteristics of ALK- and BIA ALCL pathology, which is clearly needed in order to identify critical therapeutic vulnerabilities. To address the gaps in knowledge, we applied an unbiased high throughput CRISPR screening in ALCL, and identified an unexpected role of the IL-1R-MyD88 pathway in supporting ALK- and BIA ALCL. The IL-1R signaling pathway is a key mediator of immunity and inflammation and has been shown to play a critical role in many solid tumors; however, its role in lymphoid malignancies has not been established. Indeed, our preliminary studies provide the first unequivocal evidence that IL-1R1 pathway plays an essential role in supporting ALK- and BIA ALCL cell survival. Clinically, we found that IL-1 receptor and IL-1α expression are consistently elevated in primary ALK- cases, and this is correlated with IL-1R signaling activation (p-IRAK4 level) in primary samples. Moreover, using RNA-seq analysis, we identified a set of IL-1R pathway regulated genes in ALK- ALCL that overlapped significantly with signatures reflecting JAK-STAT3 activity and TH17/TH1 phenotyping. Finally, a highly specific IRAK4 inhibitor shows promising activity against ALK- and BIA ALCL in vitro and in a mouse xenograft model. Altogether, these findings provide strong support for our hypothesis that the IL-1R pathway promotes ALK- and BIA ALCL pathogenesis, and that targeting this pathway could be a novel therapeutic strategy in these diseases. In this study, we will test our hypothesis through the following aims: 1) Elucidation of the exact role of IL-1R pathway in ALK- and BIA ALCL, 2) Understanding of mechanisms regulating this pathway and its relationship to recurrent genetic lesions in ALCL, and 3) Validation of the IL-1R pathway as a novel therapeutic target in these malignancies. The proposed studies should provide critical insights into the molecular circuitry that drives these types of ALCL and, consequently, result in the development of novel targeted therapeutic strategies for these distinct lymphoproliferative disorders.