Oncogenic Nras signaling in leukemic stem cell transformation
Oncogenic Nras signaling in leukemic stem cell transformation
批准号:
9028457
负责人:
Qing Li
金额:
$38.75万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-03-01 至 2021-02-28
关键词:
AddressAllelesBiochemicalBloodCISH geneCell ProliferationCell physiologyClonal ExpansionDefectDiseaseEpigenetic ProcessExperimental ModelsGeneticGenetic TranscriptionGoalsHematopoietic NeoplasmsHematopoietic stem cellsHumanInduced MutationJAK2 geneKnock-outKnockout MiceKnowledgeLeadMEKsMalignant NeoplasmsMediatingModelingMolecularMusMutateMutationMyeloproliferative diseaseNeoplastic Cell TransformationOncogenesOncogenicPopulationProcessRegulationRelapseResearchRoleSignal TransductionStem cellsTestingTumor Suppressor Genesbasecell transformationdesigngenetic analysisinnovationleukemialeukemic stem cellleukemogenesismutantnew therapeutic targetnovel therapeutic interventionoverexpressionprogenitorself-renewalsmall molecular inhibitortargeted treatmenttherapy development
中文摘要
摘要
癌基因和抑癌基因突变转化正常造血干细胞
细胞(HSC)在多步骤的过程中转化为白血病干细胞(LSC)。作为……的第一步
白血病发生,“白血病前”突变异常调节HSC功能促进克隆性
通过增加扩散、竞争力和自我更新进行扩张。LSC预科课程还包括
通过额外的突变转化为LSCs。瞄准前LSC和LSC具有潜在的
以消除白血病。尽管许多癌基因和抑癌基因已经被
有人建议将正常的HSCs转化为LSCs,但对哪些信号转导机制知之甚少
这一转变的基础是机制,以允许开发针对LSCs前驱的治疗方法
和LSC。我们研究的长期目标是确定信号机制,通过
癌基因和肿瘤抑制基因将正常的HSCs转化为LSCs。克隆扩增
很难在实验中概括,因为驱动HSCs进入循环的突变
通常会导致HSC自我更新减少和HSC耗尽。我们最近发现,一个
在人类白血病中常见的致癌NRAS突变G12D,异常调节HSCs和
将它们转变为具有更强的扩散性、竞争力和自我更新的Pre-LSC。这个
这项建议的目的是确定NRAS诱导的信号机制
转型。根据我们的初步结果,我们的中心假设是JAK2/STAT5
信号转导在NRAS诱导的前LSCs转化过程中起关键作用
向LSC转型。我们将通过以下方法来检验这一假设:1)确定
NrasG12D激活STAT5对HSC功能进行动态调节;2)确定JAK2在NrasG12D中的作用
3)确定JAK2/STAT5信号在FULL中的作用
转换后的LSC。这种方法是创新的,因为1)它利用了我们新的
建立了克隆扩增模型;2)结合了小鼠遗传分析和细胞和
对稀有种群进行生化分析以研究前LSCs和LSCs的信号机制
LSC,以及3)它评估非规范RAS效应器的作用
致癌RAS在与白血病发生高度相关的人群中的作用。建议数
这项研究意义重大,因为它有望促进对信号转导的了解
从正常HSC向LSCs转化的潜在机制,并因此告知
针对前LSCs和LSCs的新型治疗干预措施,以根除白血病。
英文摘要
ABSTRACT
Mutations of oncogenes and tumor suppressor genes transform normal hematopoietic stem
cells (HSC) into leukemic stem cells (LSC) in a multi-step process. As the first step of
leukemogenesis, the “pre-leukemia” mutations dys-regulate HSC functions to promote clonal
expansion by increasing proliferation, competitiveness and self-renewal. Pre-LSCs are further
transformed into LSCs by additional mutations. Targeting pre-LSCs and LSCs has the potential
to eliminate leukemia. Although many oncogenes and tumor suppressor genes have been
proposed to transform normal HSCs to LSCs, very little is known about what signaling
mechanism underlies this transformation to allow development of therapies to target pre-LSCs
and LSCs. The long term goal of our research is to identify signaling mechanisms through which
oncogenes and tumor suppressor genes transform normal HSCs into LSCs. Clonal expansion
has been difficult to recapitulate experimentally because mutations that drive HSCs into cycling
often lead to reduced HSC self-renewal and HSC depletion. We recently found that an
oncogenic Nras mutation commonly found in human leukemias, G12D, dys-regulates HSCs and
transform them into pre-LSC with increased proliferation, competitiveness and self-renewal. The
objective of this proposal is to identify the signaling mechanism underlying this Nras induced
transformation. Based on our preliminary results, our central hypothesis is that JAK2/STAT5
signaling is critical in the Nras induced transformation to pre-LSCs and further mediates
transformation to LSCs. We will test this hypothesis by 1) Identify the mechanism by which
NrasG12D activates STAT5 to dys-regulate HSC functions; 2) Define the role of JAK2 in NrasG12D
induced HSC dys-regulation and 3) determine the role of JAK2/STAT5 signaling in fully
transformed LSCs. The approach is innovative because 1) it takes advantage of our newly
developed clonal expansion model; 2) it combines mouse genetic analysis and cellular and
biochemical analysis on rare populations to investigate signaling mechanisms in pre-LSCs and
LSCs, and 3) it evaluates the role of non-canonical Ras effectors that may be responsible for
the effects of oncogenic Ras in a population highly relevant to leukemogenesis. The proposed
research is significant because it is expected to advance knowledge of the signaling
mechanisms underlying the transformation from normal HSCs to LSCs, and therefore to inform
novel therapeutic intervention that will target pre-LSCs and LSCs to eradicate leukemia.
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