Project 2

项目2

基本信息

项目摘要

Our long-term goal is to elucidate molecular mechanisms of aberrant gene control in cancer and develop innovative treatment strategies to improve the survival of children with refractory cancers such as AML. The objective of this project, which is the next logical step towards this goal as part of our collaborative U54 consortium, is to define and therapeutically target the oncogenic gene expression control activity of NUP98 fusion protein complex in AML. Our central hypothesis is that NUP98 fusion proteins generate an oncogenic chromatin remodeling protein complex that induces leukemogenic gene expression, conferring aberrant leukemia cell growth and survival, and that its molecular mechanisms and therapeutic targets can be defined using an innovative integration of functional genomics and proteomics. This hypothesis is based on two essential preliminary studies that the Armstrong and Kentsis labs have recently completed (3, 6), providing the impetus for this project: 1) Discovery of the essential functional interaction between NUP98 fusion proteins and the MLL1 and NSL chromatin remodeling complexes in AML; and 2) development of strategies to define the architecture and therapeutic disassembly of cellular protein complexes. However, the precise mechanisms linking NUP98 fusion protein complex assembly and leukemogenic chromatin functions are not defined, constituting an important gap in knowledge that is required for the development of a rational therapeutic strategy to treat fusion oncoprotein-activated AML. Aim 1 will elucidate the mechanisms of leukemogenic chromatin remodeling using inducible degradation of NUP98-fusion proteins. In Aim 2, we will define the domains and interfaces involved in aberrant assembly of NUP98-fusion chromatin remodeling complexes using in situ cross-linking mass spectrometry and CRISPR domain scanning. And lastly, we will determine the anti-leukemia efficacy of targeted epigenetic and protein interaction therapies using preclinical mouse models. Successful completion of this proposal is expected to yield molecular mechanisms and effective therapies of NUP98 fusion oncoprotein and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This research will have broad significance because fusion oncoproteins and oncogenic gene expression contribute to the majority of human cancers. Finally, the complementary interactions with other projects in this U54 consortium and development of effective molecular therapies targeting NUP98 fusion proteins in AML would constitute a transformative advance in the clinical care of patients with this disease, whose cure rates remain wholly inadequate with current therapy.
我们的长期目标是阐明异常基因控制在癌症和疾病中的分子机制

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
    $ 2.56万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10900856
  • 财政年份:
    2023
  • 资助金额:
    $ 2.56万
  • 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:
    $ 2.56万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10230527
  • 财政年份:
    2019
  • 资助金额:
    $ 2.56万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10228887
  • 财政年份:
    2019
  • 资助金额:
    $ 2.56万
  • 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:
    $ 2.56万
  • 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:
    $ 2.56万
  • 项目类别:
Genome Core
基因组核心
  • 批准号:
    10228884
  • 财政年份:
    2019
  • 资助金额:
    $ 2.56万
  • 项目类别:
Genome Core
基因组核心
  • 批准号:
    10230525
  • 财政年份:
    2019
  • 资助金额:
    $ 2.56万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10228886
  • 财政年份:
    2019
  • 资助金额:
    $ 2.56万
  • 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:
    2023
  • 资助金额:
    $ 2.56万
  • 项目类别:
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  • 批准号:
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  • 财政年份:
    2023
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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:
    $ 2.56万
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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:
    $ 2.56万
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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
  • 批准号:
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  • 财政年份:
    2023
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    $ 2.56万
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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
  • 批准号:
    10435886
  • 财政年份:
    2022
  • 资助金额:
    $ 2.56万
  • 项目类别:
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
  • 资助金额:
    $ 2.56万
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Diversifying Acute Leukemia Clinical Trial Enrollment Through Multilevel Intervention
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:
    10505579
  • 财政年份:
    2022
  • 资助金额:
    $ 2.56万
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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:
    $ 2.56万
  • 项目类别:
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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    10576955
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    2022
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    $ 2.56万
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