Pre-B cell receptor signaling in acute lymphoblastic leukemia

急性淋巴细胞白血病中的前 B 细胞受体信号传导

• 批准号: 8212348
• 负责人: Markus Müschen
• 金额: $ 32.2万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212348
• 关键词: ABL1 gene; Ablation; Acute Lymphocytic Leukemia; Adult; Antibody-Producing Cells; Apoptosis; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Bone Marrow; Cell Lineage; Cells; Characteristics; Child; Chromosome abnormality; Classification; Clonal Evolution; Congenital Abnormality; Cytogenetics; Cytotoxic agent; Data; Defect; Development; Discrimination; Disease; Dose-Limiting; Drug resistance; Elements; Employee Strikes; Exhibits; Gene Rearrangement; Goals; Growth; Health; Human; Human Biology; IRF4 gene; Immune; Immune system; Individual; Lead; MLLT2 gene; MYC gene; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Non-Hodgkin' s Lymphoma; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Relapse; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Subgroup; TCF3 gene; Testing; Toxic effect; Transgenic Mice; Treatment Protocols; Tumor Suppressor Genes; Xenograft procedure; base; cancer type; chemotherapy; cytotoxic; fusion gene; improved; in vivo; leukemia; loss of function; mouse model; novel; pre-B cell receptor; receptor expression; receptor function; reconstitution; research study; response; small hairpin RNA; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Pre-B cell receptor signaling in acute lymphoblastic leukemia. B cell precursors in human bone marrow are destined to die unless they are rescued through survival signals from a successfully assembled pre-B cell receptor. For this reason, defects in components of the pre-B cell receptor signaling chain 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. In this proposal, we test the hypothesis that the developmental arrest in B cell lineage ALL predominantly reflects aberrant pre-B cell receptor function. 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 in addition to cytotoxic drug treatment seem promising to further improve therapy options for ALL patients. In preliminary studies for this proposal on 148 cases of pre-B cell-derived human ALL, we found that ALL cells carrying an E2A-PBX1- or MYC- gene rearrangement are -like normal pre-B cells- highly selected for the expression of a functional pre-B cell receptor. In striking contrast, ALL cells with other cytogenetic abnormalities (e.g. BCR-ABL1- or MLL-AF4) lack expression of a functional pre-B cell receptor in virtually all cases. In a proof-of-principle experiment, we studied pre-B cell receptor function during progressive leukemic transformation of pre-B cells in BCR-ABL1-transgenic mice: Interestingly, signaling from the pre-B cell receptor and the oncogenic BCR-ABL1 kinase are mutually exclusive and only "crippled" pre-B cells that fail to express a functional pre-B cell receptor are permissive to transformation by BCR-ABL1. As opposed to ALL cells with BCR-ABL1- or MLL-AF4-fusion gene, pre-B cell receptor signaling is active in E2A-PBX1- or MYC-transformed ALL, because these cells exhibit a vigorous Ca2+ signal in response to pre-B cell receptor engagement. Based on these findings, we hypothesize that ALL can be subdivided into two groups based on whether pre-B cell receptor signaling enables (Type I) or suppresses (Type II) leukemic growth. Studying primary human ALL xenografts and transgenic mouse models for Type I and Type II ALL, we propose in Aim 1 to establish characteristic key differences of pre-B cell receptor signaling in the two subgroups. In Aim 2, we propose to identify the requirements for pre-B cell receptor-dependent survival signaling in Type I ALL as potential targets for pharmacological inhibition. Conversely, we propose in Aim 3 to elucidate the mechanisms of pre-B cell receptor-inactivation in Type II ALL and how functional pre-B cell receptor signaling induces apoptosis in Type II ALL cells. Given that pre-B cell receptor signaling in this subgroup of ALL effectively suppresses leukemic growth, our goal in Aim 3 is to interfere with these inactivation mechanisms to restore pre-B cell receptor-dependent apoptosis-signaling in Type II ALL cells. The proposed discrimination between Type I and Type II ALL resembles the classification of mature B cell lymphoma, in which subgroups can be distinguished based on the presence (i.e. Non-Hodgkin's lymphoma) and absence (i.e. Hodgkin's lymphoma) of B cell receptor expression. The central goal of this proposal is to establish the role of pre-B cell receptor 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.

描述（由申请人提供）：急性淋巴细胞白血病中的前 B 细胞受体信号传导。人类骨髓中的 B 细胞前体注定会死亡，除非通过成功组装的前 B 细胞受体发出的生存信号来拯救它们。因此，前 B 细胞受体信号链成分的缺陷会导致人类早期 B 细胞发育严重受阻。同样，B 细胞谱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抑制。在本提案中，我们测试了以下假设：B 细胞谱系 ALL 的发育停滞主要反映了异常的前 B 细胞受体功能。 B 细胞谱系 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。尽管过去四十年取得了重大进展，但细胞毒性治疗策略最近已达到稳定水平，儿童治愈率为 80%，成人治愈率为 55%。细胞毒性药物治疗后的复发、初始耐药性和剂量限制性毒性是当前治疗方法最常见的并发症。因此，除细胞毒性药物治疗外，通路特异性治疗策略似乎有望进一步改善 ALL 患者的治疗选择。在对 148 例前 B 细胞来源的人类 ALL 病例进行的初步研究中，我们发现携带 E2A-PBX1 或 MYC 基因重排的 ALL 细胞与正常前 B 细胞一样，经过高度选择以表达功能性前 B 细胞受体。与此形成鲜明对比的是，具有其他细胞遗传学异常（例如 BCR-ABL1 或 MLL-AF4）的 ALL 细胞几乎在所有情况下都缺乏功能性前 B 细胞受体的表达。在一项原理验证实验中，我们研究了 BCR-ABL1 转基因小鼠中前 B 细胞进行性白血病转化过程中前 B 细胞受体的功能：有趣的是，来自前 B 细胞受体和致癌 BCR-ABL1 激酶的信号是相互排斥的，只有无法表达功能性前 B 细胞受体的“瘫痪”前 B 细胞才允许 BCR-ABL1 进行转化。与具有 BCR-ABL1 或 MLL-AF4 融合基因的 ALL 细胞相反，前 B 细胞受体信号传导在 E2A-PBX1 或 MYC 转化的 ALL 中活跃，因为这些细胞响应前 B 细胞受体的参与而表现出强烈的 Ca2+ 信号。基于这些发现，我们假设根据前 B 细胞受体信号传导是否促进（I 型）或抑制（II 型）白血病生长，ALL 可以细分为两类。通过研究原代人类 ALL 异种移植物以及 I 型和 II 型 ALL 的转基因小鼠模型，我们在目标 1 中建议建立两个亚组中前 B 细胞受体信号传导的特征性关键差异。在目标 2 中，我们建议确定 I 型 ALL 中前 B 细胞受体依赖性生存信号传导的要求，作为药理学抑制的潜在目标。相反，我们在目标 3 中建议阐明 II 型 ALL 中前 B 细胞受体失活的机制，以及功能性前 B 细胞受体信号传导如何诱导 II 型 ALL 细胞凋亡。鉴于该 ALL 亚组中的前 B 细胞受体信号传导有效抑制白血病生长，我们的目标 3 是干扰这些失活机制，以恢复 II 型 ALL 细胞中的前 B 细胞受体依赖性凋亡信号传导。所提出的 I 型和 II 型 ALL 之间的区分类似于成熟 B 细胞淋巴瘤的分类，其中可以根据 B 细胞受体表达的存在（即非霍奇金淋巴瘤）和不存在（即霍奇金淋巴瘤）来区分亚组。该提案的中心目标是确定前 B 细胞受体信号传导在 ALL 恶性转化和克隆进化过程中的作用，并针对其信号级联的各个组成部分，以开发针对 ALL 的新型通路特异性治疗方法。