Targeting SOX11 in Mantle Cell Lymphoma

项目摘要 套细胞淋巴瘤(MCL)是B细胞性非霍奇金淋巴瘤的一种侵袭性、致死性亚型 (NHL)的特征是t(11；14)导致Cyclin D1(CCND1)过表达，这是该病的关键诊断特征 疾病。然而，过度表达CCND1的小鼠模型不会出现B细胞淋巴增殖 典型地见于人类的MCL。Sox11转录因子在90%的MCL肿瘤中高表达 样本并与预后不良有关，然而对Sox11在体内的功能的了解一直 由于缺乏动物模型而受到限制。因此，我们制定了、广泛地描述并出版了我们的 Eμ-sox11-egfp小鼠模型2018年5月17日；131(20)：2247-2255。E-μ-sox11-egfp小鼠的发育 脾、骨髓和外周血中克隆性B细胞增多，伴有异常 免疫表型(CD5+CD19+CD23-)和BCR信号增强，与人MCL相同。 为了准确地模拟人类MCL，其中CCND1和sox11都过度表达，我们现在开发了 将Eμ-ccnd1小鼠与Eμ-sox11-egfp杂交，建立MCL小鼠模型。Sox11诱导的 我们在Eμ-sox11-egfp小鼠中观察到的表型在双转基因小鼠中显著增强，导致 致死表型，与EU-sox11小鼠相比存活率显著降低。我们的总体假设 Sox11的过表达增加了BCR信号转导，并通过其与CCND1的协同作用 MCL发病机制中的转录靶点。为了检验我们的假设，在目标1中，我们通过以下方式定义机制 其中Sox11增加了MCL中的BCR信号。在目标2中，我们将确定分子探针抑制 BTKi或BCL2i耐药MCL的体内外SOX11-DNA结合模型。在目标3中，我们确定 SOX11与CCND1在体内外协同驱动MCL的机制。 抑制sox11的治疗优势可能是显著的，因为大多数MCL患者仍在复发。 在免疫化疗后死亡，尽管出现了新的靶向治疗方法，如BTKi或BCL2i。 我们最近通过对sox11的结构建模确定了一系列新型的小分子探针， 抑制Sox11与DNA的相互作用，具有较强的体外抗MCL细胞毒作用。我们有令人兴奋的初步数据 与我们的假设一致，证明SOX11i在体外可以克服BTKi和BCL2i的耐药性。 迈克尔·王教授是MCL的主要研究员，也是这项提案的联合研究员，他已经开发出了患者- 衍生BTKi耐药和BCL2i耐药的原代MCL细胞和相应的PDX小鼠模型。 我们的建议结合了互补的元素，包括独特的转基因动物模型，独特的 抑制sox11的分子探针，耐受当前护理标准的患者来源的原发MCL模型， 和功能研究，以扩大我们对MCL发病机制的理解，以确定新的靶点和 为这种具有挑战性的疾病的患者提供治疗选择。

Project Summary Mantle Cell Lymphoma (MCL) is an aggressive, typically fatal subtype of B-cell Non-Hodgkin's Lymphoma (NHL) characterized by t(11;14) leading to Cyclin D1 (CCND1) overexpression, a key diagnostic feature of this disease. However, murine models over-expressing CCND1 do not develop B-cell lymphoproliferation characteristically seen in human MCL. The SOX11 transcription factor is overexpressed in >90% of MCL tumor samples and associated with poor prognosis, however understanding of SOX11 function in vivo has been limited by a lack of animal models. We have therefore developed, extensively characterized and published our Eμ-SOX11-EGFP mouse model in Blood 2018 May 17;131(20):2247-2255. Eμ-SOX11-EGFP mice develop an increase in clonal B cells in the spleen, bone marrow and peripheral blood, with an aberrant immunophenotype (CD5+CD19+CD23-) and increased BCR signaling identical to human MCL. To accurately model human MCL, where both CCND1 and SOX11 are overexpressed, we have now developed an additional MCL mouse model by crossing Eμ-CCND1 mice with Eμ-SOX11-EGFP. The SOX11-induced phenotype we observe in Eμ-SOX11-EGFP mice is dramatically enhanced in the double transgenic mice, leading to a lethal phenotype with significantly reduced survival as compared to Eu-SOX11 mice. Our overall hypothesis is that the overexpression of SOX11 increases BCR signaling and cooperates with CCND1 through its transcriptional targets in MCL pathogenesis. To test our hypothesis, in Aim 1, we define the mechanism by which SOX11 increases BCR signaling in MCL. In Aim 2, we will determine efficacy of molecular probes inhibiting SOX11-DNA binding in vitro and in vivo models of BTKi or BCL2i resistant MCL. In Aim 3, we determine the mechanism by which SOX11 cooperates with CCND1 in vitro and in vivo to drive MCL. The therapeutic advantages of inhibiting SOX11 may be substantial, as the majority of MCL patients still relapse after immune-chemotherapy and die despite the advent of novel targeted therapeutics such as BTKi or BCL2i. We have recently identified through structural modeling of SOX11, a family of novel small molecule probes that inhibit the SOX11-DNA interaction with potent anti-MCL cytotoxicity in vitro. We have exciting preliminary data consistent with our hypothesis to demonstrate that SOX11i can overcome BTKi and BCL2i resistance in vitro. Prof. Michael Wang, a leading MCL researcher and a co-investigator in this proposal, has developed patient- derived BTKi-resistant and BCL2i-resistant primary MCL cells and corresponding PDX murine models. Our proposal brings together complementary elements including unique transgenic animal models, unique molecular probes inhibiting SOX11, patient-derived primary MCL models resistant to current standard of care, and functional studies for expanding our understanding of MCL pathogenesis to identify new targets and therapeutic options for patients with this challenging disease.