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: 8997437
• 负责人: Markus Müschen
• 金额: $ 35.66万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997437
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Adult; B lymphoid malignancy; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BACH2 gene; 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; Dasatinib; Data; Development; Dose-Limiting; Drug resistance; Excision; Exhibits; FDA approved; Foundations; Genetic; Genetic Determinism; Genetic study; Goals; Health; Human; Individual; Lesion; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Medicine; Modeling; Nature; Outcome; Pathway interactions; Patients; Ph+ ALL; Pharmacotherapy; Pre-Clinical Model; Protein Tyrosine Kinase; Public Health; Receptor Inhibition; Receptor Signaling; Relapse; Resistance; Risk; Role; SOX4 gene; SYK gene; Signal Transduction; Signaling Molecule; Staging; 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; patient stratification; pre-B cell receptor; pre-clinical; receptor function; response; self-renewal; src Homology Region 2 Domain; success; therapeutic target; treatment strategy; validation studies

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.

描述（由申请人提供）：人骨髓中的前B细胞注定会死亡，除非它们通过成功组装的前B细胞受体（前BCR）的存活信号被拯救。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阻滞。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。尽管在过去四十年中取得了重大进展，但细胞毒性治疗策略最近达到了一个平台，儿童治愈率约为80%，成人为55%。细胞毒性药物治疗后复发、初始耐药性和剂量限制性毒性是当前治疗方法中最常见的并发症。因此，路径特异性治疗策略似乎有望进一步改善ALL患者的治疗选择。项目初期的以下关键观察结果为此次更新申请奠定了基础：所有项目可细分为两组，这两组在BCR前功能方面存在根本差异。在TCF 3重排的ALL中，前BCR信号传导在其他细胞遗传学（例如MLL重排，Ph+）ALL亚型中使能（1型）但抑制（2型）白血病转化（Trageser et al.，J Exp Med 2009）。 1型和2型ALL中的不同结果通过前BCR信号传导在正常B细胞发育的特定阶段的对比功能来反映：前BCR驱动哈代组分C'的增殖，但在组分D前B细胞中驱动分化和细胞周期停滞（Nahar et al.，Blood 2011）。 在组分C'前B细胞和1型ALL细胞中，前BCR信号传导通过激活S 0X 4促进存活信号传导（Ramezani等人，Blood 2013），而BACH 2介导BCR前检查点的阴性选择和ALL细胞的肿瘤抑制（Swaminathan等人，Nature Medicine 2013）。 在通过前BCR检查点的级分D前B细胞中，BCL 6介导存活（Duy等人，J Exp Med 2010）。同样，BCL 6促进Ph+ ALL中的存活和先前未被认识的耐药性形式（Duy等人，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）。基于这些和其他发现，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（目标 1），验证前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（目标2），并利用该信息开发前BCR途径的药理学靶向策略，并开发预测ALL患者结局并促进风险分层的生物标志物（目标3）。这个项目的中心目标是 建议是建立前BCR信号传导在ALL的恶性转化和克隆演变过程中的作用，并针对其信号级联的单个组分，以开发ALL的新途径特异性治疗方法。

项目成果

YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway.

• DOI: 10.1186/s13045-015-0132-6
• 发表时间: 2015-04-22
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Chang BH;Johnson K;LaTocha D;Rowley JS;Bryant J;Burke R;Smith RL;Loriaux M;Müschen M;Mullighan C;Druker BJ;Tyner JW
• 通讯作者: Tyner JW

Core transcriptional regulatory circuitries in cancer.

• DOI: 10.1038/s41388-020-01459-w
• 发表时间: 2020-10
• 期刊: Oncogene
• 影响因子: 8
• 作者: Chen Y;Xu L;Lin RY;Müschen M;Koeffler HP
• 通讯作者: Koeffler HP

B-cell identity as a metabolic barrier against malignant transformation.

B细胞身份是针对恶性转化的代谢障碍。

• DOI: 10.1016/j.exphem.2017.06.004
• 发表时间: 2017-09
• 期刊: Experimental hematology
• 影响因子: 2.6
• 作者: Chan LN;Müschen M
• 通讯作者: Müschen M

Identification and characterization of OSTL (RNF217) encoding a RING-IBR-RING protein adjacent to a translocation breakpoint involving ETV6 in childhood ALL.

• DOI: 10.1038/srep06565
• 发表时间: 2014-10-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Fontanari Krause LM;Japp AS;Krause A;Mooster J;Chopra M;Müschen M;Bohlander SK
• 通讯作者: Bohlander SK

IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.

• DOI: 10.1371/journal.pone.0040934
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Iacobucci I;Iraci N;Messina M;Lonetti A;Chiaretti S;Valli E;Ferrari A;Papayannidis C;Paoloni F;Vitale A;Storlazzi CT;Ottaviani E;Guadagnuolo V;Durante S;Vignetti M;Soverini S;Pane F;Foà R;Baccarani M;Müschen M;Perini G;Martinelli G
• 通讯作者: Martinelli G