PRE-B CELL RECEPTOR SIGNALING IN ACUTE LYMPHOBLASTIC LEUKEMIA

项目摘要 人类骨髓中的前B细胞注定要死亡，除非它们通过来自A细胞的生存信号被拯救。 成功组装前B细胞受体（pre-BCR）。前BCR相关信号分子的先天性缺陷 导致人类早期B细胞发育严重受阻。同样，B细胞系急性淋巴细胞白血病 (ALL)细胞在B细胞发育的早期阶段被阻滞。B细胞系ALL代表了迄今为止 儿童常见恶性肿瘤，成人也常见。尽管过去四年取得了重大进展， 几十年来，细胞毒性治疗策略最近达到了一个平台，儿童的治愈率约为80%。 成人为55%。细胞毒药物治疗后复发、初始耐药和剂量限制性毒性 是目前治疗方法中最常见的并发症。因此，特定路径 治疗策略似乎有望进一步改善ALL患者的治疗选择。 项目初期的以下主要观察结果为此次延期申请奠定了基础： ALL可以细分为两组，这两组在前BCR功能方面存在根本差异。在TCF 3中- 重排的ALL，前BCR信号使（1型），但抑制（2型）白血病转化， 其他细胞遗传学（例如，ML重排，Ph+）ALL亚型（Trageser等，J Exp Med 2009）。 <$1型和2型ALL的不同结果反映在前BCR信号传导的对比功能上， 正常B细胞发育的特定阶段：前BCR驱动哈代级分C'的增殖， 组分D前B细胞的分化和细胞周期停滞（Nahar等，Blood 2011）。 在组分C'前B细胞和1型ALL细胞中，前BCR信号通过激活 S 0X 4（Ramezani等人，Blood 2013），而BACH 2在pre-BCR检查点介导阴性选择 和ALL细胞中的肿瘤抑制（Swaminathan等人，Nature Medicine 2013）。 在通过前BCR检查点的组分D前B细胞中，BCL 6介导存活（Duy等人，J Exp Med 2010年）。同样，BCL 6促进了Ph+ ALL患者的存活率和以前未被认识到的耐药性 (Duy等，Nature 2011）和Ph+ ALL中白血病起始细胞的自我更新（Hurtz等人，J Exp Med 2011）。 根据这些和其他研究结果，我们提出了第二个项目期的三个目标，即了解 前BCR功能从增殖到分化/细胞周期停滞的机制转换（目的1），以验证前BCR功能的有效性。 BCR检查点调节剂作为遗传功能丧失模型中的潜在治疗靶点（目的2）， 利用这一信息，开发前BCR途径的药理学靶向策略， 开发生物标志物，预测ALL患者的结局并促进风险分层（目标3）。中央 该提案的目标是确定前BCR信号传导在恶性转化中的作用， ALL的克隆进化，并靶向其信号级联的单个组分， 新的途径特异性治疗ALL的方法。

PROJECT SUMMARY 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.