Polysomy 21 in Acute Lymphoblastic Leukemia

急性淋巴细胞白血病中的 21 号多体性

• 批准号: 8623111
• 负责人: David Marc Weinstock
• 金额: $ 34.24万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623111
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Address; Affect; Aneuploidy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Bone Marrow; Cell Lineage; Cell Ontogeny; Cells; Child; Chromatin; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 21; Complex; Constitutional; DNA Sequence Rearrangement; Defect; Disease; Down Syndrome; Epidemiology; Epigenetic Process; Fetal Liver; Frequencies; Genes; Goals; Growth; HMGN1 Protein; HMGN1 gene; Histone H3; Histones; Human; Human Biology; Human Chromosomes; In Vitro; Link; Lymphoid; Lysine; Malignant Neoplasms; Malignant lymphoid neoplasm; Modeling; Nucleosomes; Oncogenes; Phenotype; Phosphotransferases; Polycomb; Polysomy; Proteins; Recurrence; Relapse; Reporting; Risk; Signal Transduction; Staging; Trisomy; Wild Type Mouse; base; bcr-abl Fusion Proteins; cell transformation; gain of function; genome-wide; histone modification; human embryonic stem cell; in vivo; innovation; leukemia; leukemogenesis; loss of function mutation; member; mouse Ts1Rhr; mouse Ts65Dn; mouse model; new therapeutic target; novel strategies; promoter; public health relevance; small hairpin RNA; therapeutic target; transcriptome sequencing; tumor

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.

描述（由申请人提供）：21号多体性（染色体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。体质性21三体（唐氏综合征，DS）与B-ALL风险增加20倍相关，强烈提示因果关系。多体性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CRLF 2重排的低风险子集。然而，这种关联的机制尚不清楚。我们先前在Ts 1 Rhr小鼠的前体B细胞中鉴定了体外转化表型，Ts 1 Rhr小鼠仅在唐氏综合征关键区（DSCR）内的33个基因为三体。具体而言，B-谱系细胞从Ts 1 Rhr小鼠有增加的集落形成和无限期的系列再铺板的甲基纤维素培养的潜力。我们现在证明，Ts 65 Dn小鼠，其中含有一个较大的三倍的基因同线与人类chr。21，和Ts 1 Rhr小鼠有缺陷的B-谱系个体发育在哈代A到哈代B过渡。此外，DSCR三体性促进体内B细胞白血病与BCR-ABLJs 1 Rhr和野生型B细胞的转录组测序鉴定了DSCR三体性的特征，其与多梳阻遏复合物2（PRC 2）的靶点及其靶点，组蛋白H3上的三甲基化赖氨酸27（H3 K27 me 3）高度相关。PRC 2成分的功能获得性突变和功能丧失性突变在淋巴恶性肿瘤中很常见，但在B-ALL中并未反复发现。一个shRNA筛选，以确定DSCR基因座，抑制系列再铺板潜力的Ts 1 Rhr B细胞牵连HMGN 1（高迁移率族核小体结合结构域1），核小体重塑蛋白，增加染色质的可及性，丰富的活性启动子，并可能抑制H3 K27 me 3。我们将在这些发现的基础上，确定促进B-ALL在21多体性细胞中的机制，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体外和体内的转录和表观遗传改变 原代B细胞和B-ALL中的B系表型。在目标2中，我们将具体阐述DSCR三体通过H3 K27 me 3的改变促进B-ALL的假设。Chr.21是急性髓性白血病中第二常见的染色体，这表明这些研究的意义超出了B-ALL。最后，该项目利用创新的方法来定义和治疗靶向复发性拷贝数改变的生物学后果，这是癌症中几乎普遍存在的发现。