The paradox of myeloid leukemia of Down syndrome

唐氏综合症髓系白血病的悖论

• 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
• 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

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 唐氏综合征(DS)儿童的急性髓系白血病(AML)和骨髓发育不良(DS)是共同知道的 为髓系白血病伴发DS(ML-DS)。ML-DS患者有很高的无事件存活率(EFS) (89.9%)单用阿糖胞苷(AraC)方案治疗。相比之下，复发的ML-DS患者 尽管包括干细胞在内的抢救疗法，但疾病的临床结果极其糟糕，OS率为35%。 细胞移植，强调了提高我们对ML-DS生物学的理解和开发新的 复发性疾病患者的治疗方法。我们的研究发现，ML-DS母细胞明显更多 与来自无DS儿童的急性髓系白血病相比，AraC敏感。此外，更多的表达 21号染色体定位的胱硫醚合酶基因(CBS)与AraC敏感性增强有关。 对ML-DS细胞系的代谢图谱显示，在AraC- 与AraC敏感的ML-DS细胞系比较，表明CBS活性降低，并提示 CBS活性降低在ML-DS患者AraC耐药中起重要作用。其他代谢变化 继发于CBS的过度表达导致DS表型，包括H_2S水平升高，从而抑制 线粒体复合体IV活性，诱导线粒体功能障碍，降低氧化磷酸化 (OXPHOS)。据报道，具有获得性AraC耐药的非ds AML细胞增加了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 ML-DS母细胞对AraC敏感性增强与线粒体功能障碍和降低有关 OXPHOS是由于CBS过度表达所致。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产生抗性。此外，表达的反- 凋亡蛋白Bcl2和Mcl-1也参与了对AraC的抵抗。因此，OXPHOS、Mcl-1、 而Bcl2可能是治疗R/RML-DS的一种有前途的方法。我们对新药伊米普酮ONC213的研究， 研究发现，ONC213在非DS AML中有效抑制OXPHOS，并下调两种非DS AML中Mcl-1的表达 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细胞中均有表达。因此，ONC213和文奈德的结合可能 有效根除对AraC耐药的ML-DS细胞。我们提议的研究将1)确定哥伦比亚广播公司在 OXPHOS和AraC在ML-DS细胞中的敏感性/耐药性；2)ONC213联合万乃馨 一种靶向AraC耐药的ML-DS细胞的方法研究哥伦比亚广播公司过度表达之间的关系 而AraC的敏感性将提高我们对ML-DS生物学的理解，这也可能导致 非DS AML患者的新治疗方法。开发治疗R/R ML-DS的新方法可能会改善预后 为这群非常抗拒治疗的患者准备的。