Pathogenic Mechanisms of CSF3R Mutations in Leukemia
CSF3R突变在白血病中的致病机制
基本信息
- 批准号:8803154
- 负责人:
- 金额:$ 8.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-19 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:Advisory CommitteesAutomobile DrivingBioinformaticsBiological AssayBone MarrowBone Marrow CellsBone Marrow TransplantationCSF3 geneCancer EtiologyCell ProliferationCellsChronic Myeloid LeukemiaChronic Neutrophilic LeukemiaCommittee MembersComplexCritiquesCytokine ReceptorsDataDimerizationDiseaseDisease ProgressionEffectivenessElementsEnzymesEtiologyEventEvolutionFacultyFred Hutchinson Cancer Research CenterGene Expression ProfileGene MutationGenesGeneticGenomicsGoalsGranulocyte Colony-Stimulating FactorGranulocyte Colony-Stimulating Factor ReceptorsHematologic NeoplasmsHematopoietic NeoplasmsIndividualInstitutesInstitutionInvestigationLigandsLinkMalignant NeoplasmsMeasuresMentorsMentorshipMessenger RNAMethodsModelingMolecularMolecular EvolutionMouse Cell LineMusMutationNeutrophilic LeukemiaOncogenesOncogenicOther GeneticsPathogenesisPatientsPharmaceutical PreparationsPhasePhosphotransferasesPoint MutationPolypeptide N-acetylgalactosaminyltransferasePositioning AttributeProtein GlycosylationProteinsRNA SequencesReceptor ActivationReceptor SignalingRegulationRelative (related person)ResearchResearch PersonnelRoleSamplingSequence AnalysisSignal PathwaySignal TransductionSiteSmall Interfering RNASorting - Cell MovementTestingTherapeutic AgentsTrainingTransplantationWorkWritingbasecancer cellcancer therapychronic leukemiacombinatorialcytokineexome sequencingfunctional genomicsgenetic evolutionglycosylationin vivoinsightkinase inhibitorknock-downleukemialeukemic stem cellleukemogenesismeetingsmouse modelmutantneutrophilnew therapeutic targetnoveloutcome forecastpreventprognosticpublic health relevancereceptorreceptor functionresponsesingle cell analysissugartumor progression
项目摘要
DESCRIPTION (provided by applicant): Colony Stimulating Factor 3 Receptor (CSF3R) is activated by CSF3 (aka GCSF), the cytokine that promotes neutrophil proliferation and differentiation. We have recently identified CSF3R mutations in 59% of patients with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). The most common of these mutations, T618I, promotes ligand-independent receptor dimerization through loss of an O-linked glycosylation site. This mutation also highly activates the Janus Activated Kinase (JAK) signaling pathway and JAK kinase inhibitors were effective in mouse models and a patient with this mutation. In Aim 1 we will investigate the regulation of normal CSF3R receptor function by O-linked glycosylation. Oncogenic point mutations in SETBP1 occur in combination with CSF3R mutations, and confer poor prognosis in these diseases. In Aim 2 we will sequence patient samples and our CSF3R T618I mouse model to identify novel genetic drivers that contribute to leukemogenesis and also investigate the order of acquisition of CSF3R and SETBP1 mutations by single cell RNA sequencing. In Aim 3 we will determine the functional consequences of having both CSF3R and SETBP1 mutations for cancer progression and kinase inhibitor sensitivity. These Aims will provide fundamental insight into the regulation of normal CSF3R function, the molecular evolution of CNL/aCML, and the prognostic consequence of having multiple genetic drivers expressed. My goal is to become a successful independent investigator and a leader in the field of molecular characterization of hematologic malignancies and identification of novel therapeutic targets. During the mentored phase I will continue to receive excellent mentorship from Dr. Brian Druker, a pioneer of targeted cancer therapy and leader of the Knight Cancer Institute. I will undertake additional training in the fiel of protein-glycosylation, with guidance from my advisory committee member, Dr. Carolyn Bertozzi at UC Berkeley, and also in single cell analysis methods, guided by Dr. Jerald Radich at the Fred Hutchinson Cancer Research Center. Working with Dr. Bertozzi and Dr. Radich will allow me to expand my training outside of my institution. The proposed research will also be enhanced by guidance from Dr. Jeffrey Tyner, an expert in cancer cell signaling and mouse models, and Dr. Shannon McWeeney who will guide me in bioinformatics analysis of sequencing data. Additionally, Dr. Druker and my advisory team will assist me in navigating the transition to an independent faculty position.
描述(由申请人提供):集落刺激因子3受体(CSF 3R)由CSF 3(又名GCSF)激活,CSF 3是一种促进中性粒细胞增殖和分化的细胞因子。我们最近在59%的慢性嗜中性粒细胞白血病(CNL)和非典型慢性髓细胞白血病(aCML)患者中发现了CSF 3R突变。这些突变中最常见的是T618 I,通过失去O-连接的糖基化位点促进配体非依赖性受体二聚化。该突变还高度激活Janus活化激酶(JAK)信号通路,JAK激酶抑制剂在小鼠模型和具有该突变的患者中有效。在目的1中,我们将研究O-连接的糖基化对正常CSF 3R受体功能的调节。SETBP 1中的致癌点突变与CSF 3R突变组合发生,并在这些疾病中赋予不良预后。在目标2中,我们将对患者样本和我们的CSF 3R T618 I小鼠模型进行测序,以鉴定有助于白血病发生的新型遗传驱动因素,并通过单细胞RNA测序研究CSF 3R和SETBP 1突变的获得顺序。在目标3中,我们将确定CSF 3R和SETBP 1突变对癌症进展和激酶抑制剂敏感性的功能后果。这些目标将提供对正常CSF 3R功能的调节、CNL/aCML的分子进化以及具有多个遗传驱动因子表达的预后后果的基本见解。我的目标是成为一名成功的独立研究者,并在血液恶性肿瘤的分子表征和新的治疗靶点的识别领域的领导者。在指导阶段,我将继续接受来自Brian Druker博士的出色指导,他是靶向癌症治疗的先驱和骑士癌症研究所的领导者。我将在我的顾问委员会成员,加州大学伯克利分校的Carolyn Bertozzi博士的指导下接受蛋白质糖基化领域的额外培训,并在Fred哈钦森癌症研究中心的Jerald Radich博士的指导下接受单细胞分析方法的培训。与Bertozzi博士和Radich博士合作将使我能够在我的机构之外扩展我的培训。Jeffrey泰纳博士是癌细胞信号传导和小鼠模型方面的专家,Shannon McWeeney博士将指导我对测序数据进行生物信息学分析。Druker和我的顾问团队将帮助我过渡到独立的教师职位。
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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Julia E Maxson其他文献
SETBP1 Regulates Myst Acetyltransferase Complexes to Drive a Leukemogenic Gene Expression Program
- DOI:
10.1182/blood-2024-203971 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Hanqian L Carlson;Samantha Tauchmann;Thai Nguyen;Sarah A Carratt;Tao Liu;Theodore P Braun;Julia E Maxson - 通讯作者:
Julia E Maxson
Differentiation State Plasticity As a Mechanism of BCL2 Inhibitor Resistance in Acute Myeloid Leukemia
- DOI:
10.1182/blood-2023-175057 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
William M Yashar;Mitsuhiro Tsuchiya;Akram Taherinasab;Sara Evans-Dutson;Brendan O'Connell;Theresa Lusardi;Nicole Szczepanksi;Galip Gurkan Yardimci;Andrew C Adey;Julia E Maxson;Theodore P Braun - 通讯作者:
Theodore P Braun
Julia E Maxson的其他文献
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{{ truncateString('Julia E Maxson', 18)}}的其他基金
Role of ASXL1 in normal and abnormal granulopoiesis.
ASXL1 在正常和异常粒细胞生成中的作用。
- 批准号:
10180659 - 财政年份:2021
- 资助金额:
$ 8.06万 - 项目类别:
Mechanisms of differentiation blockade in CSF3R-mutant AML
CSF3R 突变 AML 分化阻断机制
- 批准号:
10551215 - 财政年份:2021
- 资助金额:
$ 8.06万 - 项目类别:
Role of ASXL1 in normal and abnormal granulopoiesis.
ASXL1 在正常和异常粒细胞生成中的作用。
- 批准号:
10594440 - 财政年份:2021
- 资助金额:
$ 8.06万 - 项目类别:
Role of ASXL1 in normal and abnormal granulopoiesis.
ASXL1 在正常和异常粒细胞生成中的作用。
- 批准号:
10378101 - 财政年份:2021
- 资助金额:
$ 8.06万 - 项目类别:
Mechanisms of differentiation blockade in CSF3R-mutant AML
CSF3R 突变 AML 分化阻断机制
- 批准号:
10343811 - 财政年份:2021
- 资助金额:
$ 8.06万 - 项目类别:
Pathogenic Mechanisms of CSF3R Mutations in Leukemia
CSF3R突变在白血病中的致病机制
- 批准号:
9304169 - 财政年份:2016
- 资助金额:
$ 8.06万 - 项目类别:
Pathogenic Mechanisms of CSF3R Mutations in Leukemia
CSF3R突变在白血病中的致病机制
- 批准号:
8930113 - 财政年份:2014
- 资助金额:
$ 8.06万 - 项目类别:
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