PRE-B CELL RECEPTOR SIGNALING IN ACUTE LYMPHOBLASTIC LEUKEMIA

急性淋巴细胞白血病中的前 B 细胞受体信号转导

• 批准号: 8696722
• 负责人: Markus Müschen
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-19 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696722
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Adult; B lymphoid malignancy; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BCL6 gene; BLNK gene; Biological Markers; Blood; Bone Marrow; Cell Cycle Arrest; Cell Death; Cell Lineage; Cells; Child; Clinical; Clinical Research; Clinical Trials; Clonal Evolution; Congenital Abnormality; Cytogenetics; Cytotoxic agent; DNA Sequence Rearrangement; Dasatinib; Data; Development; Dose-Limiting; Drug resistance; Excision; Exhibits; FDA approved; Foundations; Genetic; Genetic Determinism; Goals; Human; Individual; Lesion; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Medicine; Modeling; Nature; Outcome; Pathway interactions; Patients; Pre-Clinical Model; Protein Tyrosine Kinase; Public Health; Receptor Inhibition; Receptor Signaling; Relapse; Resistance; Risk; Role; SYK gene; Signal Transduction; Signaling Molecule; Staging; Stratification; TCF3 gene; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Tumor Suppression; Tyrosine Kinase Inhibitor; Validation; addiction; base; cancer cell; cell type; cytotoxic; improved; inhibitor/antagonist; killings; kinase inhibitor; leukemia; loss of function; mouse model; novel; pre-B cell receptor; pre-clinical; public health relevance; receptor function; response; self-renewal; src Homology Region 2 Domain; success; therapeutic target; treatment strategy; validation studies

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.

项目总结 人类骨髓中的前B细胞注定要死亡，除非它们通过来自 成功组装Pre-B细胞受体(Pre-BCR)。BCR前相关信号分子的先天缺陷 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性白血病 (ALL)细胞在B细胞发育的早期阶段被阻止。到目前为止，B细胞系ALL代表的 儿童常见的恶性肿瘤，成人也很常见。尽管在过去的四年中取得了重大进展 几十年来，细胞毒治疗策略最近达到了一个平台期，儿童治愈率约为80% 成年人的比例为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之一。因此，路径特定 治疗策略似乎有望进一步改善所有患者的治疗选择。 以下是最初项目期间的主要观察结果，为续签申请奠定了基础： ALL可细分为两组，这两组在BCR前功能方面有根本不同。在TCF3中- 重新排列的ALL，Pre-BCR信号使能(类型1)，但抑制(类型2)白血病转化 其他细胞遗传学(如MLL重排、Ph+)所有亚型(Trageser等人，J Exp Med 2009)。 1型和2型ALL的不同结果反映在BCR前信号转导功能的不同 正常B细胞发育的特定阶段：Pre-BCR驱动Hardy组分C‘BUT的增殖 组分D前-B细胞的分化和细胞周期停滞(Nahar等人，血液2011)。 在部分C‘Pre-B细胞和1型ALL细胞中，Pre-BCR信号通过激活 Sox4(Ramezani等人，血液2013)，而BACH2在BCR前检查点介导负选择 以及在所有细胞中的肿瘤抑制(Swminathan等人，自然医学，2013年)。 ？在通过Pre-BCR检查点的组分D Pre-B细胞中，BCL6介导存活(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)和Ph+ALL中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 Pre-BCR功能从增殖到分化/细胞周期停滞的机制转换(目标1)，以验证Pre-BCR功能 BCR检查点调节剂在遗传功能丧失模型中的潜在治疗靶点(目标2)和 利用这些信息来制定针对BCR前途径的药理学靶向策略，并 开发生物标记物以预测结果并促进急性淋巴细胞白血病患者的风险分层(目标3)。中环 这项建议的目标是建立前bcr信号在恶性转化和 ALL的克隆进化，并针对其信号级联中的单个组件进行发育 针对ALL的新的路径特异性治疗方法。