PRE-B CELL RECEPTOR SIGNALING IN ACUTE LYMPHOBLASTIC LEUKEMIA

描述(由申请人提供)：人类骨髓中的前B细胞注定要死亡，除非它们通过成功组装的前B细胞受体(Pre-BCR)的生存信号被拯救。BCR前相关信号分子的先天缺陷会严重阻碍人类早期B细胞的发育。同样，B细胞系急性淋巴细胞性白血病(ALL)细胞在B细胞发育的早期阶段被阻止。B细胞系ALL是迄今为止儿童中最常见的恶性肿瘤，在成人中也很常见。尽管在过去的40年里取得了重大进展，但细胞毒治疗策略最近达到了一个平台期，儿童的治愈率为80%，成人的治愈率为55%。细胞毒药物治疗后复发、初始耐药和剂量限制毒性是目前治疗方法中最常见的并发症。因此，特定路径的治疗策略似乎有望进一步改善所有患者的治疗选择。在最初项目期间的以下主要观察结果奠定了此次续签申请的基础：所有这些都可以细分为两组，它们在BCR前的功能方面存在根本差异。在TCF3重排的ALL中，Pre-BCR信号启用(类型1)，但抑制(类型2)其他细胞遗传学(例如，MLL重排，Ph+)所有亚型的白血病转化(Trageser等，J Exp Med 2009)。在1型和2型ALL中，前BCR信号在正常B细胞发育的特定阶段的功能对比反映了不同的结果：前BCR驱动Hardy组分C‘的增殖，但促进组分D的Pre-B细胞的分化和细胞周期停滞(Nahar等人，血液2011)。在组分C‘Pre-B细胞和1型ALL细胞中，Pre-BCR信号通过激活Sox4促进生存信号(Ramezani等人，血液2013)，而BACH2介导在Pre-BCR检查点的负选择和所有细胞中的肿瘤抑制(Swminathan等人，自然医学2013)。在通过Pre-BCR检查点的组分D Pre-B细胞中，BCL6调节生存(Duy等人，J Exp Med 2010)。同样，BCL6可促进Ph+ALL患者的存活率和一种以前未知的耐药形式(Duy等人，《自然》杂志，2011)，以及Ph+ALL患者白血病启动细胞的自我更新(Hurtz等人，J Exp Med，2011)。基于这些和其他发现，我们提出了第二个项目阶段的三个目标，即了解BCR前功能从增殖到分化/细胞周期停滞(AIM)的机制转换 1)，在遗传功能丧失模型(目标2)中验证BCR前检查点调节子作为潜在治疗靶点，并利用这一信息制定针对BCR前途径的药理学靶向策略，并开发预测结果和促进ALL患者风险分层的生物标记物(目标3)。这样做的中心目标是 建议建立前BCR信号在ALL恶性转化和克隆性进化中的作用，并针对其信号级联的单个组件，开发针对ALL的新的通路特异性治疗方法。

DESCRIPTION (provided by applicant): Pre-B cells in human bone marrow are destined to die unless they are rescued through survival signals from a successfully assembled pre-B cell receptor (pre-BCR). Congenital defects in pre-BCR-related signaling molecules cause a severe block of early B cell development in humans. Likewise, B cell lineage acute lymphoblastic leukemia (ALL) cells are arrested at early stages of B cell development. B cell lineage ALL represents by far the most frequent malignancy in children and is also common in adults. Despite significant advances over the past four decades, cytotoxic treatment strategies have recently reached a plateau with cure rates at ~80 percent for children and 55 percent for adults. Relapse after cytotoxic drug treatment, initial drug-resistance and dose-limiting toxicity are among the most frequent complications of current therapy approaches. For this reason, pathway-specific treatment strategies seem promising to further improve therapy options for ALL patients. The following key observations during the initial project period lay the foundation for this renewal application: ALL can be subdivided into two groups that fundamentally differ with respect to pre-BCR function. In TCF3- rearranged ALL, pre-BCR signaling enables (Type 1), but suppresses (Type 2) leukemic transformation in other cytogenetic (e.g. MLL-rearranged, Ph+) ALL subtypes (Trageser et al., J Exp Med 2009). The divergent outcome in Type 1 and Type 2 ALL is mirrored by contrasting functions of pre-BCR signaling at specific stages of normal B cell development: The pre-BCR drives proliferation of Hardy Fraction C' but differentiation and cell cycle arrest in Fraction D pre-B cells (Nahar et al., Blood 2011). In Fraction C' pre-B cells and Type 1 ALL cells, pre-BCR signaling promotes survival signaling by activation of SOX4 (Ramezani et al., Blood 2013), whereas BACH2 mediates negative selection at the pre-BCR checkpoint and tumor suppression in ALL cells (Swaminathan et al., Nature Medicine 2013). In Fraction D pre-B cells that passed the pre-BCR checkpoint, BCL6 mediates survival (Duy et al., J Exp Med 2010). Likewise, BCL6 promotes survival and a previously unrecognized form of drug-resistance in Ph+ ALL (Duy et al., Nature 2011) and self-renewal of leukemia-initiating cells in Ph+ ALL (Hurtz et al., J Exp Med 2011). Based on these and other findings, we propose three Aims for the second project period, namely to understand the mechanistic switch of pre-BCR function from proliferation to differentiation/cell cycle arrest (Aim 1), to validate pre- BCR checkpoint regulators as potential therapeutic targets in genetic loss-of-function models (Aim 2) and to leverage this information to develop a strategy for pharmacological targeting of the pre-BCR pathway and to develop biomarkers that predict outcomes and facilitate risk stratification for patients with ALL (Aim 3). The central goal of this proposal is to establish the role of pre-BCR signaling during malignant transformation and clonal evolution of ALL and to target individual components of its signaling cascade for the development of novel pathway-specific therapy approaches for ALL.