The paradox of myeloid leukemia of Down syndrome

唐氏综合症髓系白血病的悖论

基本信息

批准号：
10650975
负责人：
Yubin Ge
金额：
$ 39.6万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-09 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650975
关键词：
Accounting Acute Myelocytic Leukemia Acute leukemia Apoptotic BCL2 gene Biological Assay Biology Cell Line Cells Chemoresistance Child Childhood Acute Myeloid Leukemia Chromosome 21 Chromosome Mapping Classification Clinical Clinical Research Complex Cystathionine Cystathionine beta-Synthase Cysteine Cytarabine Data Development Disease-Free Survival Down Syndrome Dysmyelopoietic Syndromes Engineering Exhibits Goals In Vitro Leukemic Cell Link MCL1 gene Metabolic Mitochondria Modeling Myeloid Leukemia Null-Cell Leukemia Outcome Oxidative Phosphorylation Patients Pediatric Oncology Group Pharmaceutical Preparations Phenotype Play Production Proteins Protocols documentation Recurrent disease Refractory Relapse Reporting Research Resistance Role Salvage Therapy Secondary to Stem cell transplant Survival Rate Testing acute myeloid leukemia cell antileukemic activity chemotherapy clinically relevant complex IV high risk improved improved outcome in vivo inhibitor insight knock-down metabolomics mitochondrial dysfunction novel novel therapeutics overexpression patient subsets synergism therapy resistant translational study treatment strategy

Accounting Acute Myelocytic Leukemia Acute leukemia Apoptotic BCL2 gene Biological Assay Biology Cell Line Cells Chemoresistance Child Childhood Acute Myeloid Leukemia Chromosome 21 Chromosome Mapping Classification Clinical Clinical Research Complex Cystathionine Cystathionine beta-Synthase Cysteine Cytarabine Data Development Disease-Free Survival Down Syndrome Dysmyelopoietic Syndromes Engineering Exhibits Goals In Vitro Leukemic Cell Link MCL1 gene Metabolic Mitochondria Modeling Myeloid Leukemia Null-Cell Leukemia Outcome Oxidative Phosphorylation Patients Pediatric Oncology Group Pharmaceutical Preparations Phenotype Play Production Proteins Protocols documentation Recurrent disease Refractory Relapse Reporting Research Resistance Role Salvage Therapy Secondary to Stem cell transplant Survival Rate Testing acute myeloid leukemia cell antileukemic activity chemotherapy clinically relevant complex IV high risk improved improved outcome in vivo inhibitor insight knock-down metabolomics mitochondrial dysfunction novel novel therapeutics overexpression patient subsets synergism therapy resistant translational study treatment strategy

展开

项目摘要

Project Summary Acute myeloid leukemia (AML) and myelodysplasia in children with Down syndrome (DS) are known collectively as myeloid leukemia associated with DS (ML-DS). ML-DS patients have high event-free survival (EFS) rates (89.9%) treated exclusively with cytarabine (AraC)-based protocols. In contrast, ML-DS patients with relapsed disease have extremely poor clinical outcomes with OS rates of <35%, despite salvage therapies including stem cell transplants, highlighting the need to improve our understanding of ML-DS biology and develop novel therapies for patients with relapsed disease. Our studies have identified that ML-DS blasts are significantly more sensitive to AraC compared to AML blasts from children without DS. Further, increased expression of chromosome 21-localized gene cystathionine-ß-synthase (CBS) is linked to the enhanced AraC sensitivities. Metabolomic profiling of ML-DS cell lines revealed reduced levels of cystathionine and cysteine in the AraC- resistant lines compared to the AraC-sensitive ML-DS cell line, indicating reduced CBS activity and suggesting that decreased CBS activity plays an important role in AraC resistance in ML-DS. Other metabolic changes secondary to CBS overexpression contribute to the DS phenotype including elevated levels of H2S, which inhibits mitochondrial Complex IV activity, induces mitochondrial dysfunction, and decreases oxidative phosphorylation (OXPHOS). It has been reported that non-DS AML cells with acquired AraC resistance have increased OXPHOS and targeting OXPHOS could overcome resistance to AraC. Hence, we hypothesize that another mechanism accounting for the enhanced AraC sensitivity of ML-DS blasts relates to mitochondrial dysfunction and decreased OXPHOS due to CBS overexpression. On the other hand, refractory/relapsed (R/R) ML-DS have increased OXPHOS due to decreased CBS activity, leading to resistance to AraC. Moreover, expression of the anti- apoptotic proteins Bcl-2 and Mcl-1 also contribute to AraC resistance. Thus, co-targeting of OXPHOS, Mcl-1, and Bcl-2 may represent a promising approach to treat R/R ML-DS. Our studies of the novel imipridone ONC213, revealed that ONC213 potently suppresses OXPHOS in non-DS AML and downregulates Mcl-1 in both non-DS AML and ML-DS, and synergistically enhances the antileukemic activity of the Bcl-2 selective inhibitor, venetoclax, in both non-DS AML and ML-DS cells. Hence, the combination of ONC213 and venetoclax may effectively eradicate AraC-resistant ML-DS cells. Our proposed studies will 1) determine the role of CBS in OXPHOS and AraC sensitivity/resistance in ML-DS cells and 2) use ONC213 in combination with venetoclax as an approach to target AraC-resistant R/R ML-DS cells. Studying the relationship between CBS overexpression and AraC sensitivity will improve our understanding of ML-DS biology, which may also lead to development of new treatments for non-DS AML patients. Developing new treatments for R/R ML-DS, may improve outcomes for this very therapy-resistant subgroup of patients.

项目摘要唐氏综合症儿童（DS）中急性髓细胞性白血病（AML）和髓发育性作为与DS（ML-DS）相关的髓样白血病。 ML-DS患者具有较高的无事件生存率（EFS）率（89.9％）专门用细胞丁滨（ARAC）的方案处理。相比之下，继电器的ML-DS患者疾病的临床结果极差，OS率<35％，目的地打捞疗法，包括STEM 细胞移植，强调需要提高我们对ML-DS生物学的理解并发展新颖的需求继电器疾病患者的疗法。我们的研究已经确定ML-DS爆炸明显更多与没有DS的儿童的AML爆炸相比，对ARAC敏感。此外，增加表达染色体21位基因胱硫醚 - ß合酶（CBS）与增强的ARAC敏感性有关。 ML-DS细胞系的代谢组分析表明，ARAC-中半胱氨酸和半胱氨酸的水平降低与对ARAC敏感的ML-DS细胞系相比，耐药线，表明CBS活性降低并表明改善CBS活性在ML-DS中的ARAC耐药性中起着重要作用。其他代谢变化 CBS继发于CBS的过表达有助于DS表型，包括H2的水平升高，抑制了H2S 线粒体复合物IV活性，诱导线粒体功能障碍，并降低氧化磷酸化（Oxphos）。据报道，具有获得ARAC耐药性的非DS AML细胞具有增加的OXPHOS 靶向Oxphos可以克服对ARAC的耐药性。因此，我们假设另一种机制计算与线粒体功能障碍相关的ML-DS爆炸的ARAC灵敏度增强并改善由于CBS的过表达而引起的Oxphos。另一方面，耐火/复发（R/R）ML-DS增加了由于CBS活性恶化而导致的OXPHO，导致对ARAC的抗性。此外，抗 - 的表达凋亡蛋白Bcl-2和Mcl-1也有助于ARAC耐药性。那是oxphos，mcl-1的共同定位和Bcl-2可能代表了治疗R/R ML-DS的有前途的方法。我们对新型丙捷酮ONC213的研究，揭示ONC213可能抑制非DS AML中的OXPHOS，并在两个非DS中下调MCL-1 AML和ML-DS，并协同增强Bcl-2选择性抑制剂的抗白血病活性，在非DS AML和ML-DS细胞中，Venetoclax。因此，Onc213和Venetoclax的组合可能有效地放射抗ARAC的ML-DS细胞。我们提出的研究将1）确定CBS在 ML-DS细胞中的Oxphos和ARAC灵敏度/抗性，2）将ONC213与Venetoclax结合使用AS 一种靶向抗ARAC的R/R ML-DS细胞的方法。研究CBS过表达之间的关系 ARAC敏感性将提高我们对ML-DS生物学的理解，这也可能导致发展非DS AML患者的新疗法。为R/R ML-DS开发新的治疗方法，可能会改善结果对于这种非常耐治疗的患者亚组。