Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia

描述（由申请人提供）：ALL1 相关白血病占婴儿和治疗相关白血病的大多数。 ALL1 是果蝇 TRITHORAX (TRX) 的人类同源物，它在胚胎发育过程中建立身体模式方面发挥着关键作用。 C. Croce 和 E. Canaani 是 ALL1 的共同发现者，A. Mazo 是 TRX 的发现者。我们的目标是进一步了解 ALL1 融合蛋白如何引发白血病。由于 ALL1 和 TRX 在结构和功能上具有很强的同源性，对 TRX 的研究产生了意想不到的重要见解，不仅与 TRX 有关，也与 ALL1 相关。我们最近取得的主要成就包括：1) ALL1融合蛋白与microRNA加工酶Drosha一起与miR-191结合，上调其表达，2) ALL1相关白血病细胞系中MEIS1和HOX A10或A9的敲低会损害其致白血病性，3) TRX在转录延伸和延伸因子招募中不可或缺的作用，4) TRX依赖性转录的作用ubx 基因上游的非编码序列抑制 ubx 编码区的表达，5) 与 ALL1 融合的正常伴侣蛋白共同招募后者的靶标，6) TRX 和 ALL1 在表观遗传中的潜在作用。 在我们的研究中，我们使用高度复杂和多样化的方法，包括全基因组定位分析、全基因组表达谱、多蛋白复合物的纯化及其组分的质谱表征、体外和体内分析microRNA的加工、应用阵列筛选来检查microRNA的表达、基于慢病毒的shRNA转导到造血细胞、分析被操纵的白血病细胞的归巢、迁移和植入、分离果蝇胚胎核从那些不表达 TRX 靶标的细胞核中表达 TRX 靶标，等等。 我们坚信，对 ALL1/TRX 和 ALL1 白血病发生问题的如此广泛的研究将为基因融合介导的白血病发生和基因调控的基础提供更深入的理解和新的视野。

DESCRIPTION (provided by applicant): ALL1-associated leukemias account for the majority of infant and therapy-related leukemias. ALL1 is the human homologue of Drosophila TRITHORAX (TRX) which has a critical role in setting up the body pattern during embryonic development. C. Croce and E. Canaani are the co-discoverers of ALL1, and A. Mazo is the discoverer of TRX. Our goal is to further understand how ALL1 fusion proteins trigger leukemia. Because of the strong homology in structure and function between ALL1 and TRX, investigations of TRX have yielded unexpected important insights pertinent not only for TRX, but for ALL1 as well. Major achievements we made recently include: 1) ALL1 fusion proteins bind together with the microRNAs processor enzyme Drosha to miR-191 to upregulate its expression, 2) knockdown of MEIS1 and HOX A10 or A9 in an ALL1-associated leukemic cell line impairs its leukemogenicity, 3) indispensable role of TRX in transcriptional elongation and in recruitment of elongation factors, 4) a role of TRX-dependent transcription of non-coding sequences upstream to the ubx genes in inhibiting expression of ubx coding region, 5) co-recruitment of normal partner proteins with ALL1 fusions to targets of the latter, 6) potential role for TRX and ALL1 in Epigenetic inheritance. In our studies we use highly sophisticated and varied methodologies, including genome-wide location analysis, genome-wide expression profiling, purification of multiprotein complexes and characterization of their components by mass spectroscopy, assaying microRNAs processing in vitro and in vivo, applying array screening to examine expression of microRNAs, lentiviral-based transduction of shRNAs into hematopoietic cells, assaying homing, migration and engraftment of manipulated leukemic cells, separating Drosophila embryo nuclei that express a TRX target from those nuclei that do not, etc. We strongly believe that such a wide-angle attack on the issues of ALL1/TRX and ALL1 leukemogenesis will provide deeper understanding and new vision of the fundamentals of gene fusion-mediated leukemogenesis and of gene regulation.