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

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.

项目概要唐氏综合症儿童的急性髓系白血病 (AML) 和骨髓增生异常 (DS) 统称为与 DS 相关的骨髓性白血病 (ML-DS) 患者的无事件生存率 (EFS) 较高。 (89.9%) 仅接受基于阿糖胞苷 (AraC) 的方案治疗，相比之下，ML-DS 患者复发。尽管采取了包括干细胞治疗在内的挽救疗法，但该疾病的临床结果极差，OS 率<35% 细胞移植，强调需要提高我们对 ML-DS 生物学的理解并开发新的我们的研究发现，ML-DS 原始细胞明显更多。与没有 DS 的儿童的 AML 母细胞相比，对 AraC 更敏感。 21 号染色体定位的基因胱硫醚-β-合酶 (CBS) 与增强的 AraC 敏感性有关。 ML-DS 细胞系的代谢组学分析显示 AraC- 中的胱硫醚和半胱氨酸水平降低与 AraC 敏感的 ML-DS 细胞系相比，抗性细胞系，表明 CBS 活性降低，并提示 CBS 活性降低在 ML-DS 的 AraC 抗性中起重要作用。 CBS 过度表达继发于 DS 表型，包括 H2S 水平升高，从而抑制线粒体复合物 IV 活性，诱导线粒体功能障碍，并降低氧化磷酸化 (OXPHOS) 据报道，具有获得性 AraC 抗性的非 DS AML 细胞的 OXPHOS 增加。因此，我们寻求另一种机制。 ML-DS 母细胞 AraC 敏感性增强的原因与线粒体功能障碍有关另一方面，难治性/复发性 (R/R) ML-DS 增加。 OXPHOS 由于 CBS 活性降低，导致对 AraC 的抗性，而且抗 AraC 的表达。凋亡蛋白 Bcl-2 和 Mcl-1 也有助于 AraC 抗性，因此 OXPHOS、Mcl-1 的共同靶向。 Bcl-2 可能是治疗 R/R ML-DS 的一种有前途的方法，我们对新型咪啶酮 ONC213 的研究，揭示 ONC213 有效抑制非 DS AML 中的 OXPHOS 并下调非 DS AML 中的 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， Venetoclax，在非 DS AML 和 ML-DS 细胞中因此，ONC213 和 Venetoclax 的组合可能。我们提出的研究将 1) 确定 CBS 在中的作用。 ML-DS 细胞中的 OXPHOS 和 AraC 敏感性/耐药性以及 2) 使用 ONC213 与 Venetoclax 组合作为一种针对 AraC 抗性 R/R ML-DS 细胞的方法，研究 CBS 过度表达之间的关系。 AraC 敏感性将提高我们对 ML-DS 生物学的理解，这也可能导致针对非 DS AML 患者的新疗法开发针对 R/R ML-DS 的新疗法可能会改善预后。对于这一非常难以接受治疗的患者亚群。