Effects of p16Ink4a and Arf on B Lineage Sensescence

描述（由申请人提供）：在老化的造血系统中，淋巴祖细胞表现出严重的生长缺陷，而髓样祖细胞保持相对不受干扰。此外，老的B细胞祖细胞对转化是难治的。本申请的中心假设是，衰老对血细胞发育和白血病发生模式的这些二分效应是由于淋巴系中作为Cdkn 2a基因座产物的p16 Ink 4a和Arf蛋白的优先表达。目的1将确定p16 Ink 4a和Arf在B淋巴细胞生成的何时和哪个阶段表达，并确定它们的表达如何影响B祖细胞的生长和存活。目的2将使用功能丧失和获得方法来确定p16 Ink 4a和Arf对B细胞发育中年龄相关性下降的相对贡献，并确定下调其表达是否可以逆转该过程。我们实验室最近的研究表明，造血祖细胞的恶性能力以反映衰老的方式演变。目的3将再次使用功能丧失和获得的方法来确定p16 Ink 4a和/或Arf在衰老B谱系细胞中的表达如何成为这种白血病发生模式的基础。这些研究的一个重要目标是开发概念验证数据，表明诱导转化淋巴祖细胞衰老将具有治疗价值。除了提供对衰老对B细胞谱系的影响的见解之外，这些研究的结果将提供“概念证明”数据，即操纵p16 Ink 4a和Arf的表达将在使老年人的B淋巴细胞生成恢复活力和治疗白血病方面具有价值。 公共卫生相关性：伴随衰老的B细胞产生减少被认为是老年人免疫力下降的原因之一。如果能更好地理解这一过程，就可能开发出旨在恢复B细胞生产的疗法。此外，本提案中的实验与理解白血病发生的模式有关，并可能提出治疗淋巴细胞白血病的新方法。

DESCRIPTION (provided by applicant): In the aging hematopoietic system, lymphoid progenitors exhibit severe growth defects, while myeloid progenitors remain relatively unperturbed. Furthermore, old B cell progenitors are refractory to transformation. The central hypothesis of this application is that these dichotomous effects of aging on blood cell development and patterns of leukemogenesis are due to the preferential expression of the p16Ink4a and Arf proteins, which are products of the Cdkn2a locus, in the lymphoid lineage. Aim 1 will define when and at which stages of B lymphopoiesis expression of p16Ink4a and Arf occurs and determine how their expression affects the growth and survival of B cell progenitors. Aim 2 will use both loss and gain of function approaches to define the relative contribution of p16Ink4a and Arf to the age-related declines in B cell development and determine whether down-regulating their expression can reverse that process. Recent studies from our laboratory have shown that the malignant capacity of hematopoietic progenitors evolves in a manner that mirrors aging. Aim 3 will again use loss and gain of function approaches to determine how expression of p16Ink4a and/or Arf in aging B lineage cells underlies this pattern of leukemogenesis. An important goal of these studies is to develop proof of concept data showing that induction of senescence in transformed lymphoid progenitors will be of therapeutic value. In addition to providing insights into the effects of aging on the B cell lineage, the results of these studies will provide `proof of concept' data that manipulating the expression of p16Ink4a and Arf will be of value in rejuvenating B lymphopoiesis in the aged and treating leukemia. PUBLIC HEALTH RELEVANCE: Reduced B cell production that accompanies aging is thought to be one reason for the decline in immunity in the elderly. If this process could be better understood, it could lead to the development of therapies designed to rejuvenate B cell production. In addition, the experiments in this proposal are relevant to understanding patterns of leukemogenesis and may suggest novel approaches for treating lymphoid leukemias.