Polysomy 21 in Acute Lymphoblastic Leukemia

描述(申请人提供)：多倍体21(Chr.21的额外拷贝)是B细胞急性淋巴细胞白血病(B-ALL)中最常见的非整倍体。体质21三体(唐氏综合征，DS)与B-ALL风险增加20倍相关，强烈表明两者之间存在因果联系。多倍体21也是B-ALL中最常见的体细胞获得性非整倍体，包括BCR-ABL和CRLF2重排的低风险亚群。然而，这种联系背后的机制尚不清楚。我们之前在Ts1Rhr小鼠的前体B细胞中发现了一种体外转化的表型，这些B细胞只有唐氏综合症临界区(DSCR)内的33个基因是三体的。具体地说，Ts1Rhr小鼠的B系细胞在甲基纤维素培养中有更多的克隆形成和不确定的连续复制潜力。我们现在证明，Ts65Dn小鼠和Ts1Rhr小鼠在Hardy A到Hardy B的转变中都存在B系个体发育缺陷。Ts65Dn小鼠拥有与人类Chr.21同线的基因的更大三倍。此外，DSCR三体与bcr-abl共同促进体内B细胞白血病的发生。对Ts1Rhr和野生型B细胞的转录组测序发现了DSCR三体的一个特征，该特征与多梳抑制物复合体2(PRC2)及其靶标--组蛋白H3上的三甲基化赖氨酸27(H3K27me3)高度相关。在淋巴系统恶性肿瘤中，PRC2成分的获得和功能丧失突变都是常见的，但在B-ALL中并未被反复发现。用于识别抑制Ts1Rhr B细胞中连续复制能力的DSCR基因座的shRNA筛选与HMGN1(高迁移率组核小体结合域1)有关，HMGN1是一种核小体重塑蛋白，可增加染色质的可及性，富含活性启动子，并可能抑制H3K27me3。我们将在这些发现的基础上，确定在具有21号染色体的细胞中促进B-ALL的机制，并确定这种疾病的新治疗靶点。在目标1中，我们将利用不可知的方法来定义在体外和体内潜在的转录和表观遗传变化。 原代B细胞和B-ALL的B系表型。在目标2中，我们将具体解决DSCR三体通过H3K27me3的改变促进B-ALL的假设。在急性髓系白血病中，21号染色体是第二个最常见的获得的染色体，这表明除了B-ALL外，这些研究还有更广泛的意义。最后，该项目利用创新的方法来定义和治疗反复拷贝数改变的生物学后果，这是一种在癌症中几乎无处不在的发现。

DESCRIPTION (provided by applicant): Polysomy 21 (extra copies of chr.21) is the most common aneuploidy in B-cell acute lymphoblastic leukemia (B-ALL). Constitutional trisomy 21 (Down Syndrome, DS) is associated with a 20-fold increased risk of B-ALL, strongly suggesting a causal link. Polysomy 21 is also the most common somatically-acquired aneuploidy in B-ALL, including the poor-risk subsets with BCR-ABL and CRLF2 rearrangements. Yet, the mechanisms underlying this association are unknown. We previously identified an in vitro transformed phenotype among precursor B-cells from Ts1Rhr mice, which are trisomic for only the 33 genes within the Down Syndrome Critical Region (DSCR). Specifically, B-lineage cells from Ts1Rhr mice have increased colony formation and indefinite serial replating potential in methycellulose culture. We now demonstrate that both Ts65Dn mice, which harbor a larger triplication of genes syntenic with human chr.21, and Ts1Rhr mice have a defect in B- lineage ontogeny at the Hardy A to Hardy B transition. In addition, DSCR trisomy promotes in vivo B-cell leukemogenesis in concert with BCR-ABL. Transcriptome sequencing of Ts1Rhr and wild-type B-cells identified a signature from DSCR trisomy that is highly associated with targets of the polycomb repressor complex 2 (PRC2) and its target, trimethylated lysine 27 on histone H3 (H3K27me3). Both gain- and loss-of- function mutations in PRC2 components are common in lymphoid malignancies but were not recurrently identified in B-ALL. An shRNA screen to identify DSCR loci that suppress serial replating potential in Ts1Rhr B-cells implicated HMGN1 (high mobility group nucleosome binding domain 1), a nucleosome remodeling protein that increases chromatin accessibility, enriches at active promoters and may suppress H3K27me3. We will build on these discoveries to define the mechanisms that promote B-ALL in cells with polysomy 21 and identify new therapeutic targets in this disease. In Aim 1, we will utilize agnostic approaches to define the transcriptional and epigenetic alterations underlying in vitro and in vivo B-lineage phenotypes in both primary B-cells and B-ALL. In Aim 2, we will specifically address the hypothesis that DSCR trisomy promotes B-ALL through alterations in H3K27me3. Chr.21 is the second most commonly gained chromosome in acute myelogenous leukemia, suggesting a broader significance for these studies beyond B-ALL. Finally, this project utilizes innovative approaches to define and therapeutically target the biologic consequences of recurrent copy number alterations, a nearly ubiquitous finding in cancer.