Pre-BCR and STAT5 Signaling in Acute Lymphoblastic Leukemia

急性淋巴细胞白血病中的前 BCR 和 STAT5 信号转导

• 批准号: 8444703
• 负责人: Michael Archibald Farrar
• 金额: $ 29.19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444703
• 关键词: Acute Lymphocytic Leukemia; Adaptor Signaling Protein; Adult; Apoptosis; Attenuated; Automobile Driving; B Cell Proliferation; B cell differentiation; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Birth; Cell Surface Receptors; Cells; Child; Childhood Precursor B Lymphoblastic Leukemia; Complex; Coupled; Data; Defect; Development; Disease; Feedback; Frequencies; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Grant; Histone Deacetylase; Human; IL7 gene; IL7R gene; Intervention; Lead; Malignant Neoplasms; Molecular; Mus; Mutation; Neoplasms; Outcome; Pathway interactions; Patients; Penetrance; Pharmacologic Substance; Play; Pre-B Acute Lymphoblastic Leukemia; Pre-B-Cell Leukemia; Production; Proteins; Receptor Signaling; Relative (related person); Reporting; Resistance; Role; STAT5A gene; STAT5b Transcription Factor; Signal Pathway; Signal Transduction; Staging; Testing; Transgenes; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cell transformation; gene repression; insight; leukemia; loss of function mutation; mutant; novel; outcome forecast; pre-B cell receptor; prevent; progenitor; programs; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Transformation of pre B cells results in the development of pre-B cell-Acute Lymphoblastic Leukemia (B-ALL). In children, ALL (most of which are B-ALL) are the most common form of neoplasia. Thus, while treatment for pediatric B-ALL is highly effective (~80% survival), the 20% non-responders still represent a sizeable number of children that succumb to this disease. In addition, some types of ALL have a much poorer prognosis. Finally, while ALL is less common in adults, their outcome is much worse (~40% survival). A subset of B-ALL has been characterized by defects in genes involved in pre-BCR signaling, such as the adaptor protein Blnk. To explore the role of pre-BCR signaling in ALL, we crossed mice expressing a constitutively active STAT5b transgene (STAT5b-CA) to blnk+/-, btk-/-, pkc2-/-, or nf:b1-/- mice. STAT5b-CA mice develop ALL with very low penetrance (~1-2), while blnk+/-, btk-/-, pkc2-/-, and nf:b1-/- mice have not been reported to develop leukemia with increased frequency relative to WT mice. In contrast, 50-100% of STAT5b-CA x blnk+/-, STAT5b-CA x btk-/-,STAT5b-CA x pkc2-/-, and STAT5b-CA x nf:b1-/- mice developed B cell ALL within 300 days of birth. Based on these preliminary findings we hypothesize that signals leading to STAT5 activation, coupled with defects in pre-BCR signaling, cooperate to initiate ALL. Our results suggest a novel pairing of STAT5, and defective pre-BCR signaling, as cooperative oncogene and tumor suppressor pathway, respectively, that initiate ALL. In addition, our preliminary data indicate that STAT5 and NFkB signaling pathways play mutually antagonistic roles in non-transformed pre-B cells and that perturbation of this antagonistic feedback loop plays an important role in initiating pre-B ALL. We will test this hypothesis by (i) identifying the molecular mechanisms by which STAT5 entrains pre-B cell transformation, and (ii) determining how antagonism between STAT5 and NFkB signaling pathways prevents transformation. The significance of these proposed studies is underscored by our recent observations that (i) ~35% of human patients with ALL have increased levels of STAT5 activation, and (ii) patients with elevated levels of STAT5 activation prior to treatment have much poorer outcomes than those with lower levels of STAT5 activation. In summary, these studies should provide new insights into the molecular mechanisms by which activation of STAT5, coupled with defects pre-BCR signaling promotes the development of progenitor B-ALL; such information should result in more optimal therapies for B-ALL in the future.

描述（由申请方提供）：前B细胞的转化导致前B细胞-急性淋巴细胞白血病（B-ALL）的发生。在儿童中，ALL（其中大多数是B-ALL）是最常见的肿瘤形式。因此，虽然儿科B-ALL的治疗非常有效（约80%的存活率），但20%的无应答者仍然代表了相当数量的死于这种疾病的儿童。此外，某些类型的ALL预后较差。最后，虽然ALL在成人中不太常见，但其结局要差得多（约40%的生存率）。B-ALL的一个子集的特征在于参与前BCR信号传导的基因缺陷，例如衔接蛋白Blnk。为了探索前BCR信号传导在ALL中的作用，我们将表达组成型活性STAT 5 b转基因（STAT 5 b-CA）的小鼠与blnk+/-、btk-/-、pkc 2-/-或nf：b1-/-小鼠杂交。STAT 5 b-CA小鼠发生ALL的概率非常低（~1-2），而blnk+/-、btk-/-、pkc 2-/-和nf：b1-/-小鼠未报告发生白血病的概率相对于WT小鼠增加。相比之下，50-100%的STAT 5 b-CA x blnk+/-、STAT 5 b-CA x btk-/-、STAT 5 b-CA x pkc 2-/-和STAT 5 b-CA x nf：b1-/-小鼠在出生后300天内发生了B细胞ALL。基于这些初步发现，我们假设导致STAT 5激活的信号，加上前BCR信号传导的缺陷，共同启动ALL。我们的研究结果表明，一种新的配对的STAT 5，和有缺陷的前BCR信号，作为合作的癌基因和肿瘤抑制途径，分别启动ALL。此外，我们的初步数据表明，STAT 5和NF κ B信号通路在非转化前B细胞中发挥相互拮抗作用，并且这种拮抗反馈回路的扰动在启动前B ALL中起重要作用。我们将通过（i）确定STAT 5参与前B细胞转化的分子机制，以及（ii）确定STAT 5和NF κ B信号通路之间的拮抗作用如何阻止转化来验证这一假设。我们最近的观察结果强调了这些拟议研究的重要性，即（i）约35%的ALL患者的STAT 5活化水平升高，（ii）治疗前STAT 5活化水平升高的患者的结局比STAT 5活化水平较低的患者差得多。总之，这些研究应该为STAT 5的激活以及前BCR信号传导缺陷促进祖细胞B-ALL发展的分子机制提供新的见解;这些信息应该在未来为B-ALL提供更优化的治疗方法。