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.
急性髓性白血病(AML)是一种异质性疾病,具有高度可变的临床结果。反复出现的
项目成果
期刊论文数量(0)
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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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