Targeting SOX11 in Mantle Cell Lymphoma

项目摘要 套细胞淋巴瘤（MCL）是一种侵袭性，典型的致命亚型B细胞非霍奇金淋巴瘤 (NHL)其特征在于t（11;14）导致细胞周期蛋白D1（CCND 1）过表达，这是该疾病的关键诊断特征。 疾病然而，过表达CCND 1的小鼠模型不发生B细胞淋巴增殖 典型见于人类MCL。SOX 11转录因子在>90%的MCL肿瘤中过表达 然而，对SOX 11在体内功能的理解一直是 由于缺乏动物模型而受到限制。因此，我们开发、广泛描述并发布了我们的 血液中的Eμ-SOX 11-EGFP小鼠模型2018年5月17日;131（20）：2247-2255。Eμ-SOX 11-EGFP小鼠发育 脾、骨髓和外周血中克隆性B细胞增加，伴有异常的 免疫表型（CD 5 + CD 19 + CD 23-）和增加的BCR信号传导与人MCL相同。 为了准确地模拟CCND 1和SOX 11都过表达的人MCL，我们现在开发了 通过Eμ-CCND 1小鼠与Eμ-SOX 11-EGFP杂交的额外MCL小鼠模型。SOX 11诱导的 我们在Eμ-SOX 11-EGFP小鼠中观察到的表型在双转基因小鼠中显著增强， 与Eu-SOX 11小鼠相比，具有显著降低的存活率的致死表型。我们的总体假设 SOX 11的过表达增加了BCR信号传导，并通过其与CCND 1的协同作用， MCL发病机制中的转录靶点。为了验证我们的假设，在目标1中，我们通过以下方式定义机制： 其中SOX 11增加MCL中的BCR信号传导。在目标2中，我们将确定分子探针抑制 BTKi或BCL 2 i抗性MCL的体外和体内模型中的S 0X 11-DNA结合。在目标3中，我们确定 SOX 11与CCND 1在体外和体内协同作用驱动MCL的机制。 抑制SOX 11的治疗优势可能是实质性的，因为大多数MCL患者仍然复发 免疫化疗后死亡，尽管出现了新的靶向治疗，如BTKi或BCL 2 i。 我们最近通过SOX 11的结构建模鉴定了一个新的小分子探针家族， 在体外抑制SOX 11-DNA相互作用，具有有效的抗MCL细胞毒性。我们有令人兴奋的初步数据 这与我们的假设一致，以证明SOX 11 i可以在体外克服BTKi和BCL 2 i抗性。 教授迈克尔·王，一位领先的MCL研究员和这项提议的共同研究者，已经开发了病人- 衍生的BTKi抗性和BCL 2 i抗性原代MCL细胞和相应的PDX鼠模型。 我们的提案汇集了互补元素，包括独特的转基因动物模型、独特的 抑制SOX 11的分子探针，对当前护理标准耐药的患者来源的原发性MCL模型， 和功能研究，以扩大我们对MCL发病机制的理解，以确定新的目标， 为患有这种具有挑战性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.