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Mechanisms of inv(16) acute myeloid leukemia

inv(16)急性髓性白血病的机制

基本信息

批准号：
10063846
负责人：
LUCIO H. CASTILLA
金额：
$ 42.68万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-06 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063846
关键词：
Acute Myelocytic Leukemia Apoptosis Applications Grants Automobile Driving Binding CBFB gene CRISPR/Cas technology Cell Survival Cells Chimeric Proteins Chromatin Chromosome 16 Core-Binding Factor Distant Downstream Enhancer Elements Enhancers Event Expression Profiling Genes Genetic Enhancer Element Genetic Transcription Hematopoietic stem cells Leukemic Cell MYH11 gene Maintenance Malignant Neoplasms Mediating Mus Mutation Myeloid Leukemia Myeloid Progenitor Cells Normal Cell Oncogenic Pathway interactions Patients Pharmacology Preleukemia Proteins Proto-Oncogene Proteins c-myc RUNX1 gene Regulation Relapse Role Science Specificity Techniques Testing Testis Toxic effect Transcriptional Regulation Up-Regulation Variant acute myeloid leukemia cell base chromatin modification dimer inhibitor/antagonist insight leukemia mouse model novel novel therapeutics oncogene addiction progenitor programs promoter self-renewal small hairpin RNA small molecule inhibitor transcription factor tumor

项目摘要

ABSTRACT Acute myeloid leukemia (AML) develops from dysregulated differentiation and self-renewal programs in the hematopoietic stem cells (HSCs) or early progenitors. The leukemia fusion protein CBFβ-SMMHC represses the transcription regulatory program of the core-binding factor RUNX1/CBFβ and generates preleukemic myeloid progenitor cells. These cells are susceptible to induce myeloid leukemia in cooperation with other oncogenic mutations. However, the pathways targeted by this fusion protein to induce pre-leukemic blasts, and the pathways involved in the oncogenic switch to leukemia are not known. We have developed a small molecule inhibitor of CBFβ-SMMHC activity that binds to the fusion protein with high specificity, and disrupts CBFβ-SMMHC/RUNX1 binding. As a result, RUNX1/CBFβ dimers increases their occupancy at the promoters of target genes and induces the transcription regulation of RUNX1/CBFB target genes Preliminary studies show that pharmacologic CBFβ-SMMHC inhibition induces apoptosis in inv(16) AML cells but not to other AML types or normal hematopoietic progenitors, suggesting an oncogene addiction switch. We hypothesize that CBFβ-SMMHC blocks the differentiation of preleukemic cells by disrupting expression of CBF targets, and that this event is reversible. However, the progression from preleukemia to leukemia is based on transcriptional and chromatin changes directed by CBFβ-SMMHC-mediated regulation of RUNX1/CBFβ activity. In addition, we will evaluate the hypothesis that this switch is due to the upregulation of MYC expression, and that in leukemic cells (but not in preleukemic cells) MYC activity maintains the survival programs. This hypothesis will be testes in the following three specific aims: Specific Aim 1. Determine how CBFβ-SMMHC induces MYC expression and maintains AML survival. Specific Aim 2. Elucidate the transcription and chromatin modification directed by CBFβ-SMMHC. Specific Aim 3. Determine the targets of CBFβ-SMMHC mediated pre-leukemia and leukemia initiation. In summary, the proposed studies combine our expertise in core binding factor leukemia, our mouse models for inv(16) AML and our novel pharmacologic inhibitor to investigate the mechanism of CBFβ-SMMHC directed preleukemia and the oncogene addiction in leukemia initiation and maintenance.

摘要急性髓性白血病（AML）是由白血病细胞中的分化和自我更新程序失调发展而来的。造血干细胞（HSC）或早期祖细胞。白血病融合蛋白CBFβ-SMMHC抑制核心结合因子RUNX 1/CBFβ的转录调节程序，并产生白血病前期骨髓祖细胞这些细胞与其他细胞协同作用容易诱发髓系白血病。致癌突变然而，这种融合蛋白诱导白血病前胚细胞的靶向途径，涉及致癌转变为白血病的途径尚不清楚。我们开发了一个小型的 CBFβ-SMMHC活性的分子抑制剂，以高特异性结合融合蛋白，并破坏 CBFβ-SMMHC/RUNX 1结合。结果，RUNX 1/CBFβ二聚体增加了它们在启动子处的占据率 RUNX 1/CBFB靶基因转录调控的初步研究显示药理学CBFβ-SMMHC抑制诱导inv（16）AML细胞凋亡，但不诱导其他AML细胞凋亡类型或正常造血祖细胞，这表明致癌基因成瘾开关。我们假设 CBFβ-SMMHC通过破坏CBF靶点的表达阻断白血病前期细胞的分化，该事件是可逆的。然而，从白血病前期到白血病的进展是基于转录和转录水平的。由CBFβ-SMMHC介导的RUNX 1/CBFβ活性调节指导的染色质变化。另外我们将评估这一转换是由于MYC表达上调的假设，以及白血病患者中MYC表达上调的假设。细胞（但不是白血病前期细胞）MYC活性维持生存程序。这一假设将得到验证在以下三个具体目标：具体目标1。确定CBFβ-SMMHC如何诱导MYC表达并维持AML存活。具体目标2。阐明转录和染色质修饰指导下， CBFβ-SMMHC。具体目标3。CBFβ-SMMHC介导的白血病前期和白血病靶点的确定入会仪式总之，拟议的研究联合收割机结合了我们在核心结合因子白血病方面的专业知识，我们的小鼠 inv（16）AML模型和我们的新药物抑制剂来研究CBFβ-SMMHC的机制定向白血病前期和白血病启动和维持中的癌基因成瘾。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia.

DOI：
10.1016/j.cell.2018.05.048
发表时间：
2018-06-28
期刊：
Cell
影响因子：
64.5
作者：
Pulikkan JA;Hegde M;Ahmad HM;Belaghzal H;Illendula A;Yu J;O'Hagan K;Ou J;Muller-Tidow C;Wolfe SA;Zhu LJ;Dekker J;Bushweller JH;Castilla LH
通讯作者：
Castilla LH

Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia.