HES1 mediates cell-specific consequences of Notch signaling in ALL
HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果
基本信息
- 批准号:8606348
- 负责人:
- 金额:$ 30.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute leukemiaApoptosisApoptoticB-Cell Acute Lymphoblastic LeukemiaB-LymphocytesBone MarrowCell modelCellsChIP-seqChronic Lymphocytic LeukemiaCoculture TechniquesComplexDataDevelopmentES01EquilibriumExposure toGene ExpressionGene FamilyGene TargetingGenesGoalsGrowthHumanIL2RA geneInhibition of ApoptosisLeadLigandsLinkLymphoidMeasuresMediatingMutationNotch Signaling PathwayOncogenesOncogenicOutcomePathway interactionsPatientsPhenotypePlayProteinsRegulationRepressionRoleSamplingSignal TransductionSystemT-Cell DevelopmentT-Cell LeukemiaT-Cell ProliferationT-LymphocyteUp-Regulationbasecancer therapycaspase-8cell typeclinically relevantgenome-wideinsightleukemialeukemogenesismRNA Expressionnotch proteinnovelnovel strategiespreventpublic health relevancereceptortumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Notch signaling is a highly conserved pathway which plays many critical roles throughout development, and is dysregulated during oncogenesis. The consequences of Notch signaling vary by cell type and depend on poorly characterized downstream mechanisms. We and others have observed contrasting roles for Notch in T and B lymphocytes and leukemias which share a common lymphoid precursor. In T cells, Notch promotes commitment and expansion, and constitutive activation leads to T cell proliferation and leukemogenesis. In contrast, Notch signaling inhibits B cell commitment and leads to growth arrest and apoptosis in normal and leukemic B cells. We have found that the Notch downstream gene HES1 is sufficient to induce growth arrest and apoptosis in B cell leukemias, but not T cell leukemias. These findings suggest that HES1 may play a critical role in determining the cell type- specific consequences of Notch signaling. The goal of this project is to elucidate the mechanism(s) by which HES1 alters the consequences of Notch signaling. We propose to use acute leukemia subtypes as a model for these cell-specific differences, and will characterize the role of HES1 in T cell versus B cell leukemias. Our results suggest that PARP1 interaction may be one mechanism, where PARP1 regulates HES1 function and leads to PARP1 cleavage and pro-apoptotic consequences. In addition, HES1 may have an alternate repertoire of transcriptional targets leading to divergent consequences. In Aim 1 we define the cell context-dependent regulation of the HES1 transcriptional complex, with a novel role for PARP1 in altering HES1 function and ties HES1 to the apoptotic cascade. Aim 2 characterizes the transcriptional consequences of HES1 signaling using genome-wide ChIP-SEQ and expression analysis, and characterization of two HES1-regulated genes which may contribute to Notch/HES1-mediated growth inhibition and apoptosis. In Aim 3 we propose to validate our hypothesis in leukemia patient samples through characterization of Notch pathway activation and exploration of the effects of the Notch ligands on these patient samples. Defining the cell context-dependent differences across acute leukemia subtypes will provide important insights into the mechanisms behind the diverse roles of Notch. These insights will inform our understanding of Notch signaling in development and oncogenesis, and may allow us to "tip-the-balance" from Notch-mediated oncogenesis to growth suppression, defining a new paradigm for cancer therapy.
描述(由申请人提供):Notch信号传导是一种高度保守的途径,在整个发育过程中起着许多关键作用,并且在肿瘤发生过程中均失调。 Notch信号传导的后果因细胞类型而异,取决于较差的下游机制。我们和其他人在T和B淋巴细胞和白血病中观察到Notch的对比作用,这些作用具有共同的淋巴前体。在T细胞中,Notch促进承诺和扩张,构成激活导致T细胞增殖和白血病发生。相反,Notch信号传导抑制了B细胞的承诺,并导致正常和白血病B细胞的生长停滞和凋亡。我们发现,下游基因HES1足以诱导B细胞白血病的生长停滞和凋亡,而不是T细胞白血病。这些发现表明,HES1可能在确定Notch信号的细胞类型特定后果中起关键作用。 该项目的目的是阐明HES1改变Notch信号的后果的机制。我们建议将急性白血病亚型作为这些细胞特异性差异的模型,并将表征Hes1在T细胞与B细胞白血病中的作用。我们的结果表明,PARP1相互作用可能是一种机制,其中PARP1调节HES1功能并导致PARP1裂解和促凋亡后果。此外,HES1可能具有转录靶标的替代曲目,从而导致不同的后果。 在AIM 1中,我们定义了HES1转录复合物的细胞上下文依赖性调节,在改变HES1功能并将HES1与凋亡级联相关联的PARP1方面具有新的作用。 AIM 2表征了HES1信号传导使用全基因组CHIP-SEQ和表达分析的转录后果,以及两个HES1调节基因的表征,这可能有助于Notch/Hes1介导的生长抑制和凋亡。在AIM 3中,我们建议通过表征Notch途径激活并探索Notch配体对这些患者样品的影响,以验证白血病患者样本中的假设。 定义急性白血病亚型之间的细胞环境依赖性差异将提供对Notch各种作用背后机制的重要见解。这些见解将使我们对发育和肿瘤发生中的凹口信号传导的理解,并可能使我们从缺口介导的肿瘤形成到生长抑制,从而“使平衡”“平衡”,从而定义了用于癌症治疗的新范式。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Notch activation inhibits AML growth and survival: a potential therapeutic approach.
- DOI:10.1084/jem.20121527
- 发表时间:2013-02-11
- 期刊:
- 影响因子:0
- 作者:Kannan S;Sutphin RM;Hall MG;Golfman LS;Fang W;Nolo RM;Akers LJ;Hammitt RA;McMurray JS;Kornblau SM;Melnick AM;Figueroa ME;Zweidler-McKay PA
- 通讯作者:Zweidler-McKay PA
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Patrick A Zweidler-McKay其他文献
Pediatric Preclinical Testing Consortium Evaluation of the Anti-CD123 Antibody-Drug Conjugate, IMGN632, Against Patient-Derived Xenograft Models of Pediatric Acute Lymphoblastic Leukemia
- DOI:
10.1182/blood-2022-159867 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Richard B Lock;Kathryn Evans;Joanna Randall;Stephen W Erickson;Eric J Earley;Steven Neuhauser;Tim Stearns;Vivek Philip;Beverly A Teicher;Krystal Watkins;Callum M Sloss;Patrick A Zweidler-McKay;Malcolm A Smith - 通讯作者:
Malcolm A Smith
Patrick A Zweidler-McKay的其他文献
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{{ truncateString('Patrick A Zweidler-McKay', 18)}}的其他基金
HES1 mediates cell-specific consequences of Notch signaling in ALL
HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果
- 批准号:
8039259 - 财政年份:2010
- 资助金额:
$ 30.07万 - 项目类别:
HES1 mediates cell-specific consequences of Notch signaling in ALL
HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果
- 批准号:
7888527 - 财政年份:2010
- 资助金额:
$ 30.07万 - 项目类别:
HES1 mediates cell-specific consequences of Notch signaling in ALL
HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果
- 批准号:
8212523 - 财政年份:2010
- 资助金额:
$ 30.07万 - 项目类别:
HES1 mediates cell-specific consequences of Notch signaling in ALL
HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果
- 批准号:
8434006 - 财政年份:2010
- 资助金额:
$ 30.07万 - 项目类别:
Notch-Mediated Apoptosis in Human B Cell Malignancies
Notch 介导的人类 B 细胞恶性肿瘤中的细胞凋亡
- 批准号:
7285227 - 财政年份:2004
- 资助金额:
$ 30.07万 - 项目类别:
Notch-Mediated Apoptosis in Human B Cell Malignancies
Notch 介导的人类 B 细胞恶性肿瘤中的细胞凋亡
- 批准号:
6775294 - 财政年份:2004
- 资助金额:
$ 30.07万 - 项目类别:
Notch-Mediated Apoptosis in Human B Cell Malignancies
Notch 介导的人类 B 细胞恶性肿瘤中的细胞凋亡
- 批准号:
6914994 - 财政年份:2004
- 资助金额:
$ 30.07万 - 项目类别:
Notch-Mediated Apoptosis in Human B Cell Malignancies
Notch 介导的人类 B 细胞恶性肿瘤中的细胞凋亡
- 批准号:
7473281 - 财政年份:2004
- 资助金额:
$ 30.07万 - 项目类别:
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