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: 8230503
• 负责人: Michael Archibald Farrar
• 金额: $ 31.06万
• 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/8230503
• 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. PUBLIC HEALTH RELEVANCE: Acute Lymphoblastic Leukemia (ALL) is the most common form of cancer in children. The studies supported by this grant will determine how deregulation of a molecule called STAT5 and a signaling pathway involving a cell surface receptor called the pre-BCR causes ALL. Our studies have implications for treatments directed at curing acute lymphoblastic leukemia and should lead to the development of new target molecules for pharmaceutical intervention in ALL.

描述（由申请人提供）：前B细胞的转化导致前B细胞急性淋巴母细胞白血病（B- all）的发展。在儿童中，ALL（大多数为b型ALL）是最常见的肿瘤形式。因此，虽然儿童B-ALL的治疗非常有效（约80%的生存率），但20%的无应答者仍然代表了相当数量的儿童死于这种疾病。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，但其预后要差得多（存活率约为40%）。B-ALL的一个亚群以参与bcr前信号传导的基因缺陷为特征，如衔接蛋白blk。为了探索前bcr信号在ALL中的作用，我们将表达组成活性STAT5b转基因（STAT5b- ca）的小鼠与blnk+/-、btk-/-、pkc2-/-或nf:b1-/-小鼠杂交。STAT5b-CA小鼠发生ALL的外显率非常低（~1-2），而blnk+/-、btk-/-、pkc2-/-和nf:b1-/-小鼠发生白血病的频率相对于WT小鼠没有增加的报道。相比之下，50-100%的STAT5b-CA x blnk+/-、STAT5b-CA x btk-/-、STAT5b-CA x pkc2-/-和STAT5b-CA x nf:b1-/-小鼠在出生300天内发生B细胞ALL。基于这些初步发现，我们假设导致STAT5激活的信号，加上bcr前信号的缺陷，共同引发ALL。我们的研究结果表明，STAT5和有缺陷的bcr前信号通路分别作为癌基因和肿瘤抑制通路的新配对，引发ALL。此外，我们的初步数据表明，STAT5和NFkB信号通路在未转化的前b细胞中起相互拮抗的作用，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STAT5携带前b细胞转化的分子机制，以及（ii）确定STAT5和NFkB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研究的重要性，即(i) ~35%的ALL患者STAT5激活水平升高，（ii）治疗前STAT5激活水平升高的患者预后比STAT5激活水平较低的患者差得多。综上所述，这些研究应该为STAT5的激活以及bcr前信号缺陷促进B-ALL祖细胞发育的分子机制提供新的见解；这些信息将在未来为B-ALL提供更优的治疗方法。