Exploring leukemogenic mechanism using genomic analysis and mouse genetics.

白血病是一种肿瘤状态，细胞分裂、分化和凋亡失控导致造血祖细胞无调控的克隆性增殖，这些异常的分子基础最终应归因于白血病基因组的遗传改变。因此，识别这些基因变化对于理解白血病的发生机制至关重要。本研究的目的是利用先进的微阵列技术探索白血病基因组中的遗传异常，确定其分子靶点，并通过利用小鼠遗传学分析靶分子来阐明白血病的发生机制。在这项研究中，我们利用高密度寡核苷酸微阵列(CNAG)建立了一个强大的癌症基因组拷贝数检测系统，并综合分析了白血病基因组中拷贝数的变化。我们分析了总共886个白血病样本，发现了大量拷贝数异常，包括那些通常在多个样本中涉及的拷贝数异常。由于极高的分辨率，可能与白血病发生相关的候选基因在许多异常区域被唯一地识别出来。Blimp1是在ATL的6q21纯合缺失中发现的这样的靶点之一。有趣的是，以Blimp1为靶标的条件性小鼠表现出淋巴结肿大和脾肿大。此外，我们发现它在原代ATL样本中发生突变，当在Hela细胞中表达时，诱导细胞停滞在G1和G2期，表明其具有肿瘤抑制功能。

Leukemia is a neoplastic state in which deregulated cell division, differentiaion, and apoptosis lead to unregulated clonal proliferation of hematopoietic progenitors and the molecular basis for these abnormalities should be finally ascribed to the genetic alterations in leukemia genome. Thus the identification of those genetic changes is of crucial importance for the understanding of leukemogeneic mechanism. The purpose of this study is exploring leukemia genomes for genetic abnormalities using advanced microarray technologies, identifying their molecular targets and clarifying the leukemogenic mechanism through analysis of the target molecules using mouse genetics. In this study, we newly developed a robust system for copy number detection of cancer genome using high-density oligonucleotide microarrays (CNAG) and comprehensively analyzed copy number alterations in leukemia genomes. We analyzed a total of 886 leukemia samples and found numerous copy number abnormalities, including those that are commonly involved in multiple samples. Due to the extremely high resolution, the candidate gene that might be relevant to leukemogenesis was uniquely identified for many abnormal regions. Blimp1 is one of such target found in a homozygous deletion at 6q21 in ATL. Interestingly, conditional Blimp1 targeted mice show lymphonode swelling as well as splenomegaly. In addition, we revealed that it is mutated in primary ATL samples and when expressed in Hela cells, induces cell arrest at both G1 and G2 phases, indicating its tumor suppressive function.