Genome Core
基因组核心
基本信息
- 批准号:10228884
- 负责人:
- 金额:$ 2.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAdult Acute Myeloblastic LeukemiaAffectBiologyCRISPR libraryCRISPR screenChemicalsChildhood Acute Myeloid LeukemiaChimeric ProteinsChromosomal RearrangementClinicalClustered Regularly Interspaced Short Palindromic RepeatsCodeCollaborationsCustomData AnalysesDevelopmentDiseaseElementsExperimental ModelsFrequenciesFusion Oncogene ProteinsFutureGene FusionGene RearrangementGenesGenetic ScreeningGenetic TranscriptionGenomeGenomicsGoalsHOXA9 geneHematopoietic NeoplasmsLeadMalignant - descriptorMediatingMolecularNuclear Pore Complex ProteinsPathway interactionsPatientsPharmacologic SubstancePre-Clinical ModelProteinsRegimenReportingResearchResearch PersonnelScanningTestingTherapeuticValidationWorkdensityeffective therapygene panelgene translocationgenome editinggenome-wideinnovationinsightleukemialeukemogenesisnew therapeutic targetnovelnovel therapeuticsoutcome forecastpediatric patientssuccesstargeted treatmenttherapeutic target
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)
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:
$ 2.28万 - 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:
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:
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