Genetic Analysis of Polarity

摘要： 人类和果蝇血液系统的发育机制表明 惊人的相似大多数基因的形成和成熟所必需的 果蝇血细胞在人类中是保守的，并且大多数与 造血系统恶性肿瘤 我们已经发现了一个新的基因，zfrp 8，控制细胞增殖， 造血器官淋巴腺zfrp 8中的几个功能丧失等位基因导致 淋巴腺大量增生，未成熟血细胞过度增殖， 以及其他组织的严重生长延迟。 Zfrp 8和它的人类直系同源物PDCD 2具有>50%的同源性。PDCD 2出现 与人类血液恶性肿瘤有关这一结论是基于其调控 通过BCL 6（B细胞淋巴瘤6）癌基因及其染色体定位到一个区域 染色体6 q27，经常在人类淋巴瘤中缺失。在一些淋巴瘤中， PDCD 2存在于正常淋巴细胞的细胞质中，但在正常淋巴细胞中未检测到。 提示该基因在恶性淋巴细胞中可能具有类似的功能 在果蝇和人类中的增殖。 在白血病患者的骨髓和血液中， 比正常形式的PDCD 2，PDCD 2？33，在健康样本中未检测到 对照PDCD2？33在我们测试的所有癌细胞系中发现，因此 与增加的细胞增殖和肿瘤发生水平相关。因为 果蝇PDCD 2/zfrp 8功能丧失表型，血细胞强烈增生， PDCD 2？33在恶性组织中，我们提出， PDCD2？33代表蛋白质的异常/致癌形式。 我们的实验旨在确定zfrp 8在正常淋巴中的功能。 腺发育和其他组织的生长在果蝇，并在表征 另外的基因，其中一些我们已经鉴定，与zfrp 8一起起作用。我们 还建议在脊椎动物中定义PDCD 2的基因产物，并研究 它们在正常和恶性细胞中的功能。

Abstract: The developmental mechanisms of human and Drosophila blood systems show remarkable parallels. Most genes essential for the formation and maturation of Drosophila hemocytes are conserved in humans, and the majority is associated with hematopoietic malignancies. We have identified a new gene, zfrp8, controlling cell proliferation of the hematopoietic organs, the lymph glands. Several loss-of-function alleles in zfrp8 cause enormous hyperplasia of the lymph glands, over-proliferation of immature blood cells, and severe growth delay in other tissues. Zfrp8 and its human ortholog, PDCD2, are >50% homologous. PDCD2 appears to be involved in human blood malignancies. This conclusion is based on its regulation by the BCL6 (B-cell lymphoma 6) oncogene and its chromosomal localization to a region of chromosome 6q27, frequently deleted in human lymphomas. In some lymphomas, PDCD2 is present in the cytoplasm of normal lymphocytes, but is not detected in malignant lymphocytes, indicating that the gene may have similar function in cell proliferation in Drosophila and humans. In the bone marrow and blood of leukemia patients, we have detected a smaller than normal form of PDCD2, PDCD2?33, that is not detected in samples from healthy controls. PDCD2?33 is found in all the cancer cell lines we have tested and thus correlates with increased levels of cell proliferation and oncogenesis. Because of the Drosophila PDCD2/zfrp8 loss-of-function phenotype, strong hyperplasia of hemocytes, and the high level of expression of PDCD2?33 in malignant tissues, we propose that PDCD2?33 represents an abnormal/oncogenic form of the protein. Our experiments are aimed at defining the function of zfrp8 in normal lymph gland development and in growth of other tissues in Drosophila, and at characterizing additional genes, a few of which we have already identified, functioning with zfrp8. We also propose to define the gene products of PDCD2 in vertebrates, and to investigate their function in normal and malignant cells.