ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

急性髓系白血病中的异常信号传导

• 批准号: 10668471
• 负责人: Alex Kentsis
• 金额: $ 47.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668471
• 关键词: Acetylation; Acute Myelocytic Leukemia; Acute leukemia; Adult; Apoptosis; Benchmarking; Binding; Biological Markers; Biology; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Chemoresistance; Child; Combination Drug Therapy; Communication; Complex; DNMT3a; Dependence; Development; Disease; Engineering; Epigenetic Process; Exhibits; Functional disorder; Fusion Oncogene Proteins; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Human; Knowledge; Lead; Leukemic Cell; Link; MLL gene; Malignant Neoplasms; Mission; Molecular; Nature; Oncogenes; Oncogenic; Outcome; Patient Care; Patients; Peptides; Productivity; Proteomics; Public Health; Refractory; Research; Research Project Grants; Resistance; Signal Transduction; Stem cell transplant; Techniques; Technology; Testing; Therapeutic; Translating; Treatment Efficacy; United States National Institutes of Health; Xenograft procedure; antileukemic activity; cell growth; chemotherapy; clinical care; clinically relevant; cohort; design; effective therapy; functional genomics; high risk; improved; in vivo; inhibitor; innovation; insight; leukemia; leukemia relapse; leukemia treatment; loss of function mutation; molecular subtypes; molecular targeted therapies; mouse model; novel; peptidomimetics; pharmacologic; pre-clinical; preclinical study; prospective; refractory cancer; restoration; small molecule inhibitor; therapeutic target; therapeutically effective; transcription factor; treatment strategy

Project Summary Despite intense efforts, the long-term cure rates of patients with acute myeloid leukemia are inadequate. Resistance to chemotherapy is prevalent, and targets for molecular therapies are only beginning to be defined. For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes of AML, but their molecular pathophysiology and pharmacologic accessibility remain poorly defined. We have now found that leukemogenic gene expression in AML requires distinct molecular interactions between the pioneer transcription factor MYB and its coactivator CBP. Remarkably, peptidomimetic inhibitors of MYB transcriptional coactivation exhibit potent anti-leukemia activity in most molecular subtypes of AML while sparing healthy cells. The central hypothesis of this proposal is that defining and blocking the molecular mechanisms of aberrant transcriptional coactivation in AML will lead directly to improved therapies for patients. Aim 1 will define the molecular mechanisms of aberrant activation of leukemic MYB transcription factor complexes that control oncogenic gene expression. Aim 2 will pursue the preliminary evidence that peptidomimetic and targeted small molecule inhibitors can be used to dismantle leukemic transcriptional complexes in vivo and develop effective therapeutic strategies using accurate genetic and patient-derived preclinical mouse models. Successful completion of this project is expected to yield essential molecular mechanisms and effective therapies of aberrant transcription factors and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This should have broad and lasting significance for understanding and treating refractory leukemias in particular and human cancer generally.

项目总结

项目成果

Integrative Proteogenomics Using ProteomeGenerator2.

• DOI: 10.1021/acs.jproteome.3c00005
• 发表时间: 2023-07
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Nathaniel Kwok;Zita E H Aretz;Sumiko Takao;Zheng Ser;P. Cifani;A. Kentsis

Towards comprehensive and quantitative proteomics for diagnosis and therapy of human disease.

致力于诊断和治疗人类疾病的综合和定量蛋白质组学。

• DOI: 10.1002/pmic.201600079
• 发表时间: 2017-01
• 期刊: Proteomics
• 影响因子: 3.4
• 作者: Cifani P;Kentsis A
• 通讯作者: Kentsis A

Disabling an oncogenic transcription factor by targeting of control kinases.

通过靶向对照激酶来禁用致癌转录因子。

• DOI: 10.18632/oncotarget.25971
• 发表时间: 2018
• 期刊: Oncotarget
• 作者: Vakoc,ChristopherR;Kentsis,Alex
• 通讯作者: Kentsis,Alex

Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center.

• DOI: 10.1002/pbc.26002
• 发表时间: 2016-08
• 期刊: Pediatric blood & cancer
• 影响因子: 3.2
• 作者: Ortiz MV;Kobos R;Walsh M;Slotkin EK;Roberts S;Berger MF;Hameed M;Solit D;Ladanyi M;Shukla N;Kentsis A
• 通讯作者: Kentsis A