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Interrogating the minor spliceosome to understand and treat leukemia

研究小剪接体以了解和治疗白血病

基本信息

批准号：
10669013
负责人：
Omar Abdel-Wahab
金额：
$ 64.6万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669013
关键词：
AKT Signaling Pathway Adaptor Signaling Protein Affect Amino Acids Biology Blood Cells Bone Marrow Cells Clonality Collaborations Complex Cytokine Signaling DNA Data Development Dysmyelopoietic Syndromes Enzymes Event Exhibits Gene Expression Genes Genetic Guanosine Health Hematopoiesis Hematopoietic Heterozygote Human Introns Knockout Mice Link Malignant - descriptor Malignant Neoplasms Messenger RNA Minor Mitogen-Activated Protein Kinases Modeling Molecular Mus Mutagenesis Mutate Mutation Myeloid Leukemia Myeloproliferative disease Open Reading Frames PI3K/AKT PTEN gene Pathogenesis Patient Care Patients Pattern Physicians Process Proteins Proteome Publishing RNA RNA Degradation RNA Splicing Recurrence Role SRSF2 gene Scientist Signal Pathway Signaling Molecule Spliceosomes Therapeutic Translating Tumor Suppressor Proteins Ubiquitination Work cohort comparative conditional knockout defined contribution demethylation efficacy testing experimental study functional genomics hematopoietic stem cell self-renewal inhibitor leukemia leukemogenesis loss of function mutant novel novel therapeutic intervention novel therapeutics response self-renewal transcriptome ubiquitin ligase

项目摘要

SUMMARY Genes encoding RNA splicing factors are the most common class of mutations in patients with myelodysplastic syndromes (MDS) and are also common across all other forms of myeloid malignancies. These leukemia- associated “spliceosomal mutations” primarily occur in four genes: SF3B1, SRSF2, U2AF1, and ZRSR2. In three of these four genes (SF3B1, SRSF2, and U2AF1), the mutations occur at specific amino acid residues in a heterozygous manner (so-called “mutational hotspots”) and cause gain/alteration of function. In contrast, mutations in ZRSR2 occur throughout the open reading frame and appear to confer loss of function. Moreover, ZRSR2's normal function makes it unique amongst the commonly mutated RNA splicing factors in leukemias: ZRSR2 is the only frequently mutated factor that primarily functions in the recognition of a rare class of introns known as “minor introns.” Thus, ZRSR2 mutations are significantly enriched in leukemia and exhibit a unique genetic spectrum and function amongst recurrent spliceosomal mutations, yet they are comparatively poorly studied and understood compared to mutations in SF3B1, SRSF2, and U2AF1. Here, we propose to determine the mechanistic, functional, and therapeutic consequences of ZRSR2 mutations in leukemia. Our interdisciplinary team consists of a physician-scientist with expertise in leukemia biology and patient care (Abdel-Wahab) and a basic scientist with expertise in RNA splicing and functional genomics (Bradley). As minor introns are far more conserved than are most other introns, we hypothesize that a cross-species comparisons of the effects of ZRSR2 loss will be particularly useful for understanding how molecular alterations in splicing drive malignant transformation. In addition, we hypothesize that aberrant splicing induced by ZRSR2 loss will enable novel therapeutic approaches. In preliminary experiments, we generated a Zrsr2 conditional knockout (cKO) mouse, assembled a relevant patient cohort, characterized the transcriptomes of our Zrsr2 cKO mouse and ZRSR2-mutant MDS, and performed a functional genomic screen to model and prioritize ZRSR2-regulated splicing events. These studies revealed that ZRSR2 mutations cause mis-splicing of a compact set of genes, that Zrsr2 loss promotes aberrant and increased hematopoietic stem cell self-renewal, that simultaneous ZRSR2 and TET2 collaborate to drive malignancy, and that mis-splicing of specific downstream targets of ZRSR2 promotes clonality. We propose to build on these preliminary studies as follows: Aim 1, Determine how ZRSR2 mutations dysregulate the transcriptome and proteome in leukemia; Aim 2, Determine how disruption of ZRSR2-regulated splicing events drives clonal advantage; Aim 3, Identify the functional basis for the frequent co-occurrence of ZRSR2 and TET2 mutations in leukemia. The significance of these studies is that they will elucidate mechanistic and functional connections between ZRSR2 mutations, RNA mis-splicing, and the initiation of myeloid neoplasms. The health relatedness is that the proposed work may reveal new therapies for MDS and leukemia that specifically kill ZRSR2-mutant cells.

总结编码RNA剪接因子的基因是骨髓增生异常综合征患者中最常见的一类突变。骨髓增生异常综合征（MDS）是常见的，并且在所有其他形式的骨髓恶性肿瘤中也很常见。白血病- 相关的“剪接体突变”主要发生在四个基因中：SF 3B 1、SRSF 2、U2 AF 1和ZRSR 2。在这四个基因中的三个（SF 3B 1，SRSF 2和U2 AF 1），突变发生在特定的氨基酸残基，杂合方式（所谓的“突变热点”）并引起功能的获得/改变。与此相反， ZRSR 2中的突变发生在整个开放阅读框中，并且似乎导致功能丧失。此外，委员会认为， ZRSR 2的正常功能使其在白血病中常见的突变RNA剪接因子中是独特的： ZRSR 2是唯一一种主要在识别一类罕见内含子中起作用的频繁突变因子称为“次要内含子”因此，ZRSR 2突变在白血病中显著富集，并表现出独特的在复发性剪接体突变之间的遗传谱和功能，但它们相对较差与SF 3B 1，SRSF 2和U2 AF 1中的突变相比，研究和理解。在这里，我们建议确定ZRSR 2的机制，功能和治疗后果，白血病的突变我们的跨学科团队由一位具有白血病专业知识的医生和科学家组成生物学和病人护理（阿卜杜勒瓦哈卜）和基础科学家与RNA剪接和功能基因组学（布拉德利）。由于次要内含子比大多数其他内含子保守得多，我们假设，跨物种比较ZRSR 2缺失的影响将特别有助于理解剪接中的分子改变驱动恶性转化。此外，我们假设，由ZRSR 2缺失诱导的剪接将使新的治疗方法成为可能。在初步实验中，我们产生Zrsr 2条件性敲除（cKO）小鼠，组装相关患者群组，表征我们的Zrsr 2 cKO小鼠和ZRSR 2突变型MDS的转录组，并进行功能基因组筛选对ZRSR 2调控的剪接事件进行建模和优先排序。这些研究表明，ZRSR 2突变导致一组紧凑的基因的错误剪接，即Zrsr 2缺失促进异常和增加的造血干细胞细胞自我更新，同时ZRSR 2和TET 2合作驱动恶性肿瘤， ZRSR 2的特异性下游靶标促进克隆性。我们建议在这些初步研究的基础上，目的：1、研究ZRSR 2突变对白血病转录组和蛋白质组的影响; 目的2，确定ZRSR 2调节的剪接事件的破坏如何驱动克隆优势;目的3，确定白血病中ZRSR 2和TET 2突变频繁共存的功能基础。的这些研究的意义在于，它们将阐明 ZRSR 2突变、RNA错误剪接和髓系肿瘤的发生健康相关性是，这项工作可能会揭示出治疗MDS和白血病的新疗法，这种疗法可以特异性地杀死ZRSR 2突变细胞。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulation and therapeutic targeting of RNA splicing in cancer.

DOI：
10.1038/s43018-022-00384-z
发表时间：
2022-05
期刊：
NATURE CANCER
影响因子：
22.7
作者：
Stanley, Robert F.;Abdel-Wahab, Omar
通讯作者：
Abdel-Wahab, Omar

The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.

DOI：
10.1172/jci.insight.167270
发表时间：
2023-06-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Dunker, William;Zaver, Shivam A.;Pineda, Jose Mario Bello;Howard, Cameron J.;Bradley, Robert K.;Woodward, Joshua J.
通讯作者：
Woodward, Joshua J.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.

DOI：
10.1182/bloodadvances.2023009675
发表时间：
2023-09-12
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Mccarter, Joseph G. W.;Nemirovsky, David;Famulare, Christopher A.;Farnoud, Noushin;Mohanty, Abhinita S.;Stone-Molloy, Zoe S.;Chervin, Jordan;Ball, Brian J.;Epstein-Peterson, Zachary D.;Arcila, Maria E.;Stonestrom, Aaron J.;Dunbar, Andrew;Cai, Sheng F.;Glass, Jacob L.;Geyer, Mark B.;Rampal, Raajit K.;Berman, Ellin;Abdel-Wahab, Omar I.;Stein, Eytan M.;Tallman, Martin S.;Levine, Ross L.;Goldberg, Aaron D.;Papaemmanuil, Elli;Zhang, Yanming;Roshal, Mikhail;Derkach, Andriy;Xiao, Wenbin
通讯作者：
Xiao, Wenbin

Splicing regulation in hematopoiesis.