Antibody V Gene Expression B Cell Lymphocytic Leukemia

我们在确定免疫球蛋白(Ig)可变区基因(V)的使用方面取得了重大进展 基因)在慢性淋巴细胞白血病(CLL)中表达。先前的研究表明免疫球蛋白V基因谱系受到限制 已经扩展，揭示了在CLL中表达的Ig可能是因为它们的结合能力而被选择 多个低亲和力的自身抗原。我们用B细胞产生了转基因小鼠，表达了这种 多反应的人类免疫球蛋白M发现这些细胞可以分化为边缘带(MZ)，即记忆型B型 细胞。这种MZ B细胞与CLL细胞具有相同的基因表达谱。这些和其他新的 发展的CLL转基因小鼠模型将使我们能够评估Ig受体信号转导是否在 在白血病发生和/或疾病进展中的作用。最近的研究表明，慢性淋巴细胞性白血病患者 表达突变免疫球蛋白的细胞比表达CLL的细胞具有更无痛的临床病程 未突变的免疫球蛋白基因。基因表达研究表明，表达未突变Ig的CLL细胞 通过相对较小的子集的差异表达来区别于更懒惰的类型 基因，其中一个编码ZAP-70。我们发现，表达这种蛋白酪氨酸激酶的CLL细胞 有更熟练的信号通过B细胞受体(BCR)复合体比不表达的CLL细胞 ZAP-70用腺病毒载体编码野生型或突变型ZAP-70的研究是 帮助解决ZAP-70是否在BCR信号转导中发挥功能作用，从而起到治疗作用 这种疾病的靶点。最后，这一项目的工作导致制定了诱导反艾滋病的战略 通过CD40连接激活的CLL细胞的白血病免疫反应。第一阶段和早期 重组腺病毒载体编码重组CD40配体(Ad-CD40-L)的II期临床试验 CD154)是对该提案所做工作的直接表现。进一步的研究可以使我们能够 改进这种方法，为患有这种疾病的患者开发真正有效的免疫疗法。

We have made significant progress in defining the use of immunoglobulin (Ig) variable region genes (V genes) in chronic lymphocytic leukemia (CLL). Prior studies suggesting restriction in the Ig V gene repertoire have been extended, revealing that the Ig expressed in CLL possibly are selected for their ability to bind multiple self-antigens with low affinity. We generated transgenic mice with B cells that express such polyreactive human IgM and found that these cells can differentiate into marginal zone (MZ), memory-type B cells. Such MZ B cells share gene expression profiles with that of CLL cells. These and other newly developed transgenic mouse models of CLL will allow us to evaluate whether Ig receptor signaling plays a role in leukemogenesis and/or disease progression. Recent studies have revealed that patients with CLL cells expressing mutated Ig have a more indolent clinical course that those with CLL cells that express unmutated Ig genes. Gene expression studies revealed that CLL cells expressing unmutated Ig could be distinguished from the more indolent type through the differential expression of a relatively small subset of genes, one of which encodes ZAP-70. We found that CLL cells that express this protein tyrosine kinase have more proficient signaling via the B cell receptor (BCR) complex than CLL cells that do not express ZAP-70. Transfection studies using adenovirus vectors encoding wild type or mutant forms of ZAP-70 are helping to resolve whether ZAP-70 plays a functional role in BCR signaling that can serve as a therapeutic target in this disease. Finally,work on this project has led to development of strategies for inducing anti- leukemia immune responses via the use of CLL cells that are activated via CD40-ligation. Phase I and early phase II clinical trials using recombinant adenovirus vectors encoding a recombinant CD40-ligand (Ad- CD154) are direct manifestations of work performed on this proposal. Further studies could enable us to refine this approach toward development of truly effective immune therapy for patients with this disease.