Targeting the Core Binding Factor tumor suppressor in MLL-fusion AML

靶向 MLL 融合 AML 中的核心结合因子肿瘤抑制因子

基本信息

批准号：
8645095
负责人：
HARTMUT GEIGER
金额：
$ 22.46万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8645095
关键词：
11q23 AML1-ETO fusion protein Accounting Acute Myelocytic Leukemia Animals Attention Biological Models Blood Cells Cancer Cell Growth Cell Proliferation Cell Survival Cell model Cells Chemotherapy-Oncologic Procedure Chimeric Proteins Chromosomal translocation Clinic Combined Modality Therapy Core-Binding Factor Cytarabine DNA Damage Data Development Disease Disease remission Dominant-Negative Mutation Doxorubicin Dysmyelopoietic Syndromes Ectopic Expression Effectiveness Event Fluorescence Resonance Energy Transfer Fusion Protein Expression Gene Mutation Genetic Models Growth Hematologic Neoplasms Human Human Development Immunodeficient Mouse In Vitro Lesion Leukemic Cell MLL-AF9 MYH11 gene Measures Mediating Modeling Molecular Mus Mutation Myeloproliferative disease Nuclear Patients Phase Point Mutation Proteins RUNX1 gene Recurrence Relapse Role Sampling Signal Transduction Small Business Innovation Research Grant Testing Therapeutic Therapeutic Effect Toxicity Tests Translating Transplantation Treatment outcome Tumor Suppressor Proteins Umbilical Cord Blood Work Xenograft Model base cancer therapy cell growth chemotherapy clinical application commercialization human cord blood CD34+ cell in vivo in vivo Model inhibitor/antagonist innovative technologies leukemia mutant novel phase 2 study pre-clinical preclinical study public health relevance small hairpin RNA small molecule t(8 21)(q22 q22)therapeutic target

项目摘要

DESCRIPTION (provided by applicant): RUNX1 is considered a beneficial tumor suppressor in myeloid neoplasms. Inhibition of RUNX1 function has been implicated as an important mechanistic event in the development of core-binding factor-(CBF)-leukemia and MLL-fusion leukemia. Inactivating RUNX1 mutations are frequently found in patients with acute myeloid leukemia (AML). However, RUNX1 mutation is usually heterozygous, complete loss of RUNX1 in AML is rare and no somatic RUNX1 mutation have been found in AMLs with common fusion proteins, such as CBF- and MLL-fusion leukemias. These data raise the possibility that a certain (low) level of RUNX1 activity is required for survival and growth of AML. We have developed human models for AML by transducing leukemogenic fusion proteins into human cord blood CD34+ cells. MLL-AF9-expressing cord blood cells cause human leukemia when transplanted into immunodeficient mice. We recently found that these AML cells critically depend on RUNX1 activity for sustained growth and survival, indicating that RUNX1 is a promising therapeutic strategy for AML. We will clarify molecular mechanisms underlying RUNX1-mediated survival/growth of AML cells and translate these findings into the clinic, using a novel RUNX1 inhibitor in murine xenograft models of human AML. This study will provide a proof of principle to the proposed strategy, and will serve as useful preclinical preliminary data for clinical application.

描述（由申请人提供）：RUNX1被认为是骨髓肿瘤中有益的肿瘤抑制因子。 RUNX1 功能的抑制被认为是核心结合因子 (CBF) 白血病和 MLL 融合白血病发展中的重要机制事件。 RUNX1 失活突变常见于急性髓系白血病 (AML) 患者。然而，RUNX1突变通常是杂合的，AML中RUNX1完全缺失的情况很少见，并且在具有常见融合蛋白的AML（例如CBF和MLL融合白血病）中未发现体细胞RUNX1突变。这些数据提出了这样的可能性：一定（低）水平的 RUNX1 活性对于 AML 的生存和生长是必需的。我们通过将致白血病融合蛋白转导至人脐带血 CD34+ 细胞中，开发了 AML 人类模型。当将表达 MLL-AF9 的脐带血细胞移植到免疫缺陷小鼠体内时，会导致人类白血病。我们最近发现这些 AML 细胞关键依赖 RUNX1 活性来持续生长和存活，表明 RUNX1 是一种有前途的 AML 治疗策略。我们将阐明 RUNX1 介导的 AML 细胞存活/生长的分子机制，并将这些发现转化为临床，在人类 AML 的小鼠异种移植模型中使用新型 RUNX1 抑制剂。这项研究将为所提出的策略提供原理证明，并将作为临床应用的有用的临床前初步数据。