Genome Core

基因组核心

基本信息

项目摘要

ABSTRACT NUP98 rearrangements are observed in up to 10% of the childhood acute myeloid leukemia (AML) and are associated with poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the NUP98-rearranged leukemias emphasize the need for novel regimens. Our central hypothesis is that NUP98-fusion oncoproteins harbor critical functional regions that are essential to their leukemogenetic potential. We also expect that NUP98-fusions will drive specific transcriptional networks, and provide potential vulnerabilities that can be exploited using CRISPR-mediated genome editing approach. We will test our hypothesis using multiple levels of CRISPR-mediated genetic screens covering genome-wide, target gene panel, and saturation protein scan. In collaboration with the Project 1 and Project 2 in this proposal, the Genome Editing Core will help provide critical insights into the molecular mechanisms by which NUP98- fusion oncoproteins lead to the development of leukemia. This work is innovative in that it will illuminate critical domains/motifs in NUP98-fusion oncoproteins, a particularly malignant disease that currently has no effective therapy. We expect that successful completion of this proposal will (1) establish a new genetic screen approach “saturation CRISPR protein scan” for a sub-protein level functional domain discovery, and (2) yield novel mechanistic information about the functional regions in the NUP98-fusion oncoproteins. The impact of this research will be of significance because (1) it provides novel therapeutic opportunities against the difficult-to-treat NUP98-rearranged leukemias, and (2) it will help identify novel functional elements in fusion oncoproteins and their associated pathways for future pharmaceutical targeting.
摘要 NUP98重排在高达10%的儿童急性髓性白血病中观察到 (AML)并且与不良预后相关。未满足的临床需求和缺乏 NUP98重排白血病的有效靶向治疗强调了对新的 养生法 我们的中心假设是NUP98融合癌蛋白具有关键的功能区域, 对他们的白血病潜能至关重要。我们还预计NUP98融合将推动 特定的转录网络,并提供潜在的漏洞,可以利用 CRISPR介导的基因组编辑方法。我们将使用多个水平来测试我们的假设 CRISPR介导的遗传筛选涵盖全基因组、靶基因组和饱和度 蛋白质扫描在本提案中,基因组与项目1和项目2合作, 编辑核心将有助于提供关键的见解,NUP98- 融合癌蛋白导致白血病的发展。 这项工作是创新的,因为它将阐明NUP98融合中的关键结构域/基序 癌蛋白,一种特别恶性的疾病,目前没有有效的治疗方法。我们预计 成功完成这项提案将(1)建立一种新的遗传筛查方法, 用于亚蛋白水平功能结构域发现的"饱和CRISPR蛋白扫描",和(2) 产生关于NUP98-融合中的功能区域的新的机制信息 癌蛋白这项研究的影响将是有意义的,因为(1)它提供了新颖的 针对难治性NUP98重排白血病的治疗机会,和(2)它 将有助于识别融合癌蛋白及其相关通路中的新功能元件 用于未来的药物靶向。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Charles G. Mullighan其他文献

Feasibility and Outcome of Post-Induction Therapy Incorporating Dasatinib for Patients with Newly Diagnosed ABL-Class Fusion B-Lymphoblastic Leukemia (ABL-class Fusion B-ALL): Children's Oncology Group AALL1131
  • DOI:
    10.1182/blood-2023-190495
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Wanda L. Salzer;Michael J. Burke;Meenakshi Devidas;Zhiguo (Bruce) Chen;Michael J. Borowitz;Andrew J Carroll;I-Ming L. Chen;Julie M. Gastier-Foster;Richard C. Harvey;Nyla A. Heerema;Charles G. Mullighan;Karen R. Rabin;Shalini C Reshmi;Cheryl L. Willman;Brent L. Wood;Naomi J. Winick;William L. Carroll;Elizabeth A. Raetz;Mignon L. Loh;Stephen P. Hunger
  • 通讯作者:
    Stephen P. Hunger
Prior Knowledge Integration Improves Relapse Prediction and Identifies Relapse Associated Mechanisms in Childhood B Cell Acute Lymphoblastic Leukemia
  • DOI:
    10.1182/blood-2023-187264
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Abhishek Vallabhbhai Koladiya;Astraea Jager;Anthony Culos;Milton Merchant;Yuxuan Liu;Lucille Stuani;Jolanda Sarno;Pablo Domizi;Charles G. Mullighan;Nima Aghaeepour;Sean Bendall;Kara L. Davis
  • 通讯作者:
    Kara L. Davis
Human Models of emNUP98/em-Rearranged Leukemia Reveal Fusion-Specific Molecular Mechanisms
  • DOI:
    10.1182/blood-2022-164686
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
    23.100
  • 作者:
    Masayuki Umeda;Nicole L. Michmerhuizen;Ryan Hiltenbrand;Juan M. Barajas;Bright Arthur;Sherif Abdelhamed;Jing Ma;Tamara Westover;Jonathan Miller;Charles G. Mullighan;Jeffery M. Klco
  • 通讯作者:
    Jeffery M. Klco
The Impact of Age and Genomics on Drug Sensitivity in 1,076 Children and Adults with B-Cell Acute Lymphoblastic Leukemia
  • DOI:
    10.1182/blood-2023-181788
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Satoshi Yoshimura;Zhenhua Li;Yoshihiro Gocho;Wenjian Yang;Kristine R Crews;Shawn H.R. Lee;Kathryn G. Roberts;Charles G. Mullighan;Mary V. Relling;Federico Antillon-Klussmann;Allen Eng Juh Yeoh;Mignon L. Loh;Mark R. Litzow;Sima Jeha;Seth E. Karol;Hiroto Inaba;Ching-Hon Pui;Marina Y. Konopleva;Nitin Jain;Wendy Stock
  • 通讯作者:
    Wendy Stock
Genetic and Functional Characterization of <em>NUP98</em>-Rearranged Leukemia
  • DOI:
    10.1182/blood-2024-210208
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Masayuki Umeda;Nicole L Michmerhuizen;Ryan Hiltenbrand;Juan M Barajas;Bright Arthur;Michael P Walsh;Guangchun Song;Jing Ma;Tamara Westover;Petri Pölönen;Cristina Mecucci;Danika Di Giacomo;Franco Locatelli;Riccardo Masetti;Salvatore Bertuccio;Martina Pigazzi;Ilaria Iacobucci;Charles G. Mullighan;Jeffery M Klco
  • 通讯作者:
    Jeffery M Klco

Charles G. Mullighan的其他文献

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{{ truncateString('Charles G. Mullighan', 18)}}的其他基金

Experimental and preclinical modeling of NUP98-rearranged acute leukemia
NUP98重排急性白血病的实验和临床前模型
  • 批准号:
    10829603
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10900856
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
Childhood Hematological Malignancies Training Program
儿童血液恶性肿瘤培训计划
  • 批准号:
    10456864
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10230527
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10230528
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10228887
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Childhood Hematological Malignancies Training Program
儿童血液恶性肿瘤培训计划
  • 批准号:
    10226110
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Experimental and preclinical modeling of NUP98-rearranged acute leukemia
NUP98重排急性白血病的实验和临床前模型
  • 批准号:
    10228882
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Genome Core
基因组核心
  • 批准号:
    10230525
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10228886
  • 财政年份:
    2019
  • 资助金额:
    $ 2.28万
  • 项目类别:

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Targeting Menin in Acute Leukemia with Upregulated HOX Genes
通过上调 HOX 基因靶向急性白血病中的 Menin
  • 批准号:
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  • 财政年份:
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  • 资助金额:
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Experimental and preclinical modeling of NUP98-rearranged acute leukemia
NUP98重排急性白血病的实验和临床前模型
  • 批准号:
    10829603
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
Rapid Acute Leukemia Genomic Profiling with CRISPR enrichment and Real-time long-read sequencing
利用 CRISPR 富集和实时长读长测序进行快速急性白血病基因组分析
  • 批准号:
    10839678
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
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A Systems Epidemiology Approach for Predicting Methotrexate Neurotoxicity in Pediatric Acute Leukemia
预测儿童急性白血病甲氨蝶呤神经毒性的系统流行病学方法
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  • 财政年份:
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抗CD25放射免疫治疗和全骨髓照射治疗复发难治性急性白血病
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    10435886
  • 财政年份:
    2022
  • 资助金额:
    $ 2.28万
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mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
  • 批准号:
    10339742
  • 财政年份:
    2022
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通过多层次干预使急性白血病临床试验招募多样化
  • 批准号:
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  • 财政年份:
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    $ 2.28万
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急性白血病微小残留病的克隆动力学和化疗耐药机制
  • 批准号:
    10351765
  • 财政年份:
    2022
  • 资助金额:
    $ 2.28万
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Anti-CD25 Radioimmunotherapy and Total Marrow Irradiation for Treatment of Relapsed and Refractory Acute Leukemia
抗CD25放射免疫治疗和全骨髓照射治疗复发难治性急性白血病
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