Antibody V Gene Expression B Cell Lymphocytic Leukemia

我们在定义免疫球蛋白（IG）可变区基因（V）的使用方面取得了重大进展 慢性淋巴细胞性白血病（CLL）中的基因）。既往研究表明IG V基因库受限 已经被扩展，揭示了在CLL中表达的IG可能是由于它们的结合能力而被选择的， 低亲和力的多种自身抗原。我们用B细胞产生了转基因小鼠， 多反应性人IgM，并发现这些细胞可以分化为边缘区（MZ），记忆型B 细胞这种MZ B细胞与CLL细胞共享基因表达谱。这些和其他新的 开发的CLL转基因小鼠模型将使我们能够评估IG受体信号传导是否在CLL中起作用。 在白血病发生和/或疾病进展中的作用。最近的研究表明，CLL患者 表达突变的IG的细胞比表达突变的CLL细胞具有更惰性的临床过程。 未突变的IG基因。基因表达研究表明，表达未突变的IG的CLL细胞可以被诱导分化。 通过一个相对较小的亚组的差异表达， 其中一个基因编码ZAP-70。我们发现表达这种蛋白酪氨酸激酶的CLL细胞 通过B细胞受体（BCR）复合物的信号传导比不表达BCR的CLL细胞更有效。 ZAP-70使用编码野生型或突变形式的ZAP-70的腺病毒载体的转染研究是 有助于解决ZAP-70是否在BCR信号传导中发挥功能作用， 针对这种疾病。最后，关于这一项目的工作导致制定了诱导反 通过使用通过CD 40连接激活的CLL细胞来产生白血病免疫反应。第一阶段和早期 使用编码重组CD 40-配体的重组腺病毒载体（Ad-1）的II期临床试验 CD 154）是对本建议书所做工作的直接体现。进一步的研究可以使我们 完善这种方法，为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.