Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia
急性髓系白血病耐药和疾病进展的分子机制
基本信息
- 批准号:9922661
- 负责人:
- 金额:--
- 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:2019-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:11q23Acute Myelocytic LeukemiaAlkylating AgentsAnabolismApoptoticBlocking AntibodiesBone MarrowBone Marrow CellsCD34 geneCREBBP geneCellsChimeric ProteinsChromosome 7Chromosome abnormalityClinicalComplexCytogeneticsCytokine ReceptorsCytokine SignalingCytotoxic ChemotherapyDiseaseDisease ProgressionDisease remissionDrug resistanceDysmyelopoietic SyndromesEmergency SituationEquilibriumEventExpression ProfilingFLT3 geneFas-associated phosphatase-1Gene ActivationGene ExpressionGenesGenetic ModelsGlycosaminoglycansGoalsGranulopoiesisGrowth Factor ReceptorsGuanine Nucleotide Exchange FactorsHOX proteinHOXA10 geneHematopoieticHumanITGB3 geneImmune responseImpairmentInnate Immune ResponseIntegrin alphaVKaryotypeMLL geneMediatingModelingMolecularMusMutationMyelopoiesisMyeloproliferative diseaseOntologyOutcomeOxidative StressPIK3CG genePathway interactionsPatientsPhagocytesPhosphorylationPoint MutationProcessProductionProgressive DiseaseProtein KinaseProtein phosphataseProteinsReceptor Protein-Tyrosine KinasesReceptor SignalingRecurrent diseaseRefractory DiseaseRegulationRelapseRepressionResistanceRoleSamplingSignal PathwaySignal TransductionStressTP53 geneTopoisomerase-II InhibitorTranscriptional Activationacute myeloid leukemia celladverse outcomeaggressive therapyautocrinebiological adaptation to stresschemotherapychromosome losscomorbiditycytokinedesigndrug relapsehomeodomainimmunoregulationinhibitor/antagonistknock-downleukemialeukemic stem cellleukemogenesismouse modelneoplasm therapynovel strategiesoutcome forecastoverexpressionpreventprognosticprotein expressionpurine/pyrimidine metabolismresponsesmall molecule inhibitortherapeutic targettranscription factortranscriptometranslational approachubiquitin-protein ligasewound
项目摘要
Acute myeloid leukemia (AML) is a heterogeneous disease with highly variable clinical outcomes. Recurring
chromosomal abnormalities permit assignment of some AML patients to favorable vs unfavorable prognostic
groups. Adverse prognosis is also associated with increased expression of a set of homeodomain transcription
factors (HoxA7-11 and Meis1) and their target genes. This expression profile is found in AML with translocation
or partial duplication of the MLL1 gene (i.e. 11q23-AML), translocations involving the MYST3 and CREBBP
genes, and a subset of cytogenetically normal (CN) AML.
We previously identified a set of common HoxA9/10 target genes that was enriched for cytokine receptors
and their pathways, including Fgf2, Tgfβ2 and β3 integrin. HoxA9 and 10 cooperate to activate these genes in
hematopoietic and leukemia stem cells (HSC and LSC). Consistent with this, we found that treatment with Fgf-
R inhibitors (Fgf-R blocking antibody or the small molecule inhibitor, nintedanib) decreased proliferation and
survival of CD34+ bone marrow cells from subjects with “Hox-profile” AML compared to samples from those
without. In preliminary studies, we found that adding nintedanib to standard induction chemotherapy significantly
prolonged remission and survival vs chemotherapy alone in a murine model of MLL1 rearranged leukemia.
HoxA9 and A10 also regulate the innate immune response, but in this case their activities are antagonistic.
During the innate immune response, activation of emergency granulopoiesis requires HoxA9, but HoxA10 is
required to terminate the process. Termination required activation of the Triad1 gene by HoxA10; a process that
involved overcoming repression by HoxA9. Triad1 is an E3 ubiquitin ligase that degrades growth factor receptors
and Mdm2. We found Triad1 knockdown accelerated leukemogenesis in a murine model of 11q23-AML.
In this murine model, we found the Lin-ckit+ LSC transcriptome was enriched for pathways involved in
cytokine production, receptor tyrosine kinase (RTK) signaling, regulation of protein kinase activity, and positive
regulation of the immune response vs control cells. We also found activation of pathways not previously
associated with 11q23-AML, including Rap1 signaling. We profiled gene expression in mice in chemotherapy-
induced remission (destined to relapse) vs chemotherapy + nintedanib (with sustained remission). We found
differences in cytokine receptor activity, Pi3k/Akt signaling, guanine nucleotide exchange factor activity,
purine/pyrimidine metabolism, oxidative stress response, and glycosamino-glycan biosynthesis.
We hypothesize that adverse prognosis in Hox-overexpressing AML is characterized by impaired regulation
of cytokine stimulated pathways and an activated stress response. These pathways represent rationale
therapeutic targets to decrease chemotherapy resistance. This hypothesis will be pursued through three aims:
Aim 1: Define the role of receptor tyrosine kinase pathways in drug resistance in Hox-overexpressing
AML. We will study RTK/PI3K signaling pathways identified in our studies in bone marrow from murine AML
models, including activity of anti-apoptotic BH3 proteins and protein phosphatase 2a (PP2a).
Aim 2: Determine the impact of Rap1 signaling on disease progression in Hox-overexpressing AML.
We will determine the role of various guanine nucleotide exchange factors on Rap or Ras activity, disease
progression, and LSC persistence during chemotherapy.
Aim 3: Investigate these pathways in AML patient samples. CD34+ bone marrow cells from AML patients
at presentation or with relapsed or refractory disease after standard chemotherapy +/- approved agents will be
analyzed. Hox-overexpressing AML will be compared to AML without increased Hox protein expression.
The goal of these studies is to identify therapeutic targets to abolish or suppress LSCs during or after
chemotherapy in adverse prognosis AML. This will be especially relevant to design new approaches to patients
who are not candidates for aggressive treatment due to refractory disease or the presence of co-morbidities.
急性髓系白血病(AML)是一种临床预后差异很大的异质性疾病。反复出现
染色体异常可以将一些AML患者的预后分为有利和不利两种情况
组。不良预后还与一组同源结构域转录增加有关
因子(HoxA7-11和Meis1)及其靶基因。此表达谱可在易位的急性髓系白血病中发现
或MLL1基因的部分复制(即11q23-AML),涉及MYST3和CREBBP的易位
基因,以及细胞遗传学正常(CN)AML的子集。
我们之前发现了一组共同的HoxA9/10靶基因,这些基因富含细胞因子受体
其途径包括FGF2、转化生长因子β2和β3整合素。HoxA9和10合作激活这些基因
造血干细胞和白血病干细胞(HSC和LSC)。与此一致,我们发现使用成纤维细胞生长因子治疗-
受体抑制物(成纤维细胞生长因子受体阻断抗体或小分子抑制物,inetedanib)可抑制细胞增殖和
“HOX-Profile”AML患者CD34+骨髓细胞存活率的比较
没有。在初步研究中,我们发现在标准诱导化疗的基础上加入九替达尼显著
在MLL1重排白血病小鼠模型中,与单纯化疗相比,延长了缓解和存活时间。
HoxA9和A10也调节先天免疫反应,但在这种情况下,它们的活性是拮抗的。
在先天免疫反应中,紧急粒系的激活需要HoxA9,但HoxA10是
终止进程所需的。终止需要HoxA10激活Triad1基因;这一过程
包括克服HoxA9的镇压。Triad1是一种E3泛素连接酶,可降解生长因子受体
和MDM2。我们在11q23-AML小鼠模型中发现Triad1基因敲除加速了白血病的发生。
在这个小鼠模型中,我们发现Lin-cKit+LSC转录组富含参与
细胞因子的产生、受体酪氨酸激酶(RTK)信号、蛋白激酶活性的调节和阳性
免疫反应与对照细胞的调节。我们还发现了以前没有激活过的通路
与11q23-AML相关,包括Rap1信号转导。我们分析了化疗过程中小鼠的基因表达-
诱导缓解(注定复发)与化疗+9tedanib(持续缓解)。我们发现
细胞因子受体活性,PI3K/Akt信号,鸟核苷酸交换因子活性,
嘌呤/嘧啶代谢、氧化应激反应和糖胺-多糖的生物合成。
我们假设HOX过表达的AML患者的不良预后以调节受损为特征。
细胞因子刺激的通路和激活的应激反应。这些途径代表了基本原理
降低化疗耐药性的治疗目标。这一假设将通过三个目标来实现:
目的1:明确受体酪氨酸激酶通路在HOX过表达耐药中的作用
AML。我们将研究我们在小鼠急性髓系白血病骨髓中发现的RTK/PI3K信号通路
模型,包括抗凋亡的BH3蛋白和蛋白磷酸酶2a(PP2A)的活性。
目的2:确定RAP1信号在HOX过表达的AML中对疾病进展的影响。
我们将确定各种鸟嘌呤核苷酸交换因子对Rap或Ras活性的作用,疾病
进展和LSC在化疗期间的持久性。
目的3:在急性髓系白血病患者样本中研究这些途径。急性髓系白血病患者的CD34+骨髓细胞
标准化疗后出现复发或难治性疾病的患者+/-批准的药物
分析过了。过表达HOX蛋白的AML将与不表达HOX蛋白的AML进行比较。
这些研究的目标是确定在治疗期间或之后取消或抑制LSC的治疗靶点。
化疗预后不良的急性髓系白血病。这对于为患者设计新的治疗方法尤其重要。
由于难治性疾病或合并疾病的存在而不适合进行积极治疗的患者。
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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Elizabeth Ann Eklund其他文献
Elizabeth Ann Eklund的其他文献
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{{ truncateString('Elizabeth Ann Eklund', 18)}}的其他基金
Molecular mechanisms for bone marrow failure and clonal progression during the innate immune response in Fanconi Anemia
范可尼贫血先天免疫反应期间骨髓衰竭和克隆进展的分子机制
- 批准号:
10348140 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia.
急性髓系白血病耐药和疾病进展的分子机制。
- 批准号:
10698907 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Identifying molecular markers that predict relapse after therapy discontinuation inchronic myeloid leukemia.
识别预测慢性粒细胞白血病治疗停止后复发的分子标记。
- 批准号:
9922662 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Identifying molecular markers that predict relapse after therapy discontinuation inchronic myeloid leukemia.
识别预测慢性粒细胞白血病治疗停止后复发的分子标记。
- 批准号:
10427231 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia
急性髓系白血病耐药和疾病进展的分子机制
- 批准号:
10265363 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Identifying molecular markers that predict relapse after therapy discontinuation inchronic myeloid leukemia.
识别预测慢性粒细胞白血病治疗停止后复发的分子标记。
- 批准号:
10291794 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Molecular mechanisms of drug resistance and disease progression in acute myeloid leukemia
急性髓系白血病耐药和疾病进展的分子机制
- 批准号:
10454870 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Molecular mechanisms for bone marrow failure and clonal progression during the innate immune response in Fanconi Anemia
范可尼贫血先天免疫反应期间骨髓衰竭和克隆进展的分子机制
- 批准号:
9895782 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Triad1 regulates myelopoiesis and functions as a leukemia suppressor
Triad1 调节骨髓细胞生成并发挥白血病抑制因子的作用
- 批准号:
8891685 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Triad1 regulates myelopoiesis and functions as a leukemia suppressor
Triad1 调节骨髓细胞生成并发挥白血病抑制因子的作用
- 批准号:
9032480 - 财政年份:2015
- 资助金额:
-- - 项目类别:
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