Polysomy 21 in Acute Lymphoblastic Leukemia

描述（由申请人提供）：21多体染色体（额外的chr副本）。21)是b细胞急性淋巴母细胞白血病（B-ALL）中最常见的非整倍体。体质21三体（唐氏综合症，DS）与B-ALL风险增加20倍相关，强烈表明两者之间存在因果关系。21多体也是B-ALL中最常见的体获得性非整倍体，包括BCR-ABL和CRLF2重排的低风险亚群。然而，这种关联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表型，这些细胞只有唐氏综合征关键区（DSCR）内的33个基因是三体的。具体来说，来自Ts1Rhr小鼠的b系细胞在甲基纤维素培养中增加了集落形成和无限序列复制潜力。我们现在证明，这两种Ts65Dn小鼠，具有更大的三倍基因与人类chr。21，并且Ts1Rhr小鼠在Hardy a向Hardy B过渡时存在B系个体发育缺陷。此外，DSCR三体与BCR-ABL一起促进体内b细胞白血病的发生。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，该特征与多梳抑制复合体2 （PRC2）的靶点及其靶点组蛋白H3上的三甲基化赖氨酸27 （H3K27me3）高度相关。PRC2成分的功能获得和功能丧失突变在淋巴恶性肿瘤中很常见，但在B-ALL中并不常见。通过shRNA筛选，发现抑制Ts1Rhr b细胞中序列复制潜能的DSCR位点涉及HMGN1（高迁移率组核小体结合结构域1），HMGN1是一种核小体重塑蛋白，可增加染色质可及性，在活性启动子处富集，并可能抑制H3K27me3。我们将在这些发现的基础上确定促进21染色体多体细胞B-ALL的机制，并确定这种疾病的新治疗靶点。在目标1中，我们将利用不可知论的方法来定义体外和体内潜在的转录和表观遗传改变

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.