Modeling and Targeting B/Myeloid Mixed Phenotype Acute Leukemia

B/骨髓混合表型急性白血病的建模和靶向

• 批准号: 10582721
• 负责人: WENYONG CHEN
• 金额: $ 21.09万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-03 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582721
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Adult; Age; Aging; Animal Model; Biogenesis; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Survival; Child; Childhood; Chronic Myeloid Leukemia; DNA Sequence Alteration; Deacetylase; Development; Disease; Disease Outcome; Drug resistance; Epigenetic Process; Future; Genomics; Hematopoietic stem cells; Histone Deacetylase; Human; Immunocompetent; Inbred BALB C Mice; Knock-out; Knowledge; Leukemic Cell; Malignant Neoplasms; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mutate; Mutation; Myelogenous; Oncogenic; Other Genetics; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Phenotype; Prognosis; Proteins; Publishing; Recurrence; Regimen; Ribosomes; Role; SIRT1 gene; Sampling; Testing; Therapeutic; Therapeutic Intervention; Transcript; Transplantation; age effect; age related; bisulfite sequencing; cell growth; disease mechanisms study; exome sequencing; genome-wide; genome-wide analysis; genomic data; hematopoietic stem cell aging; high risk; improved; in vivo; innovation; insight; knock-down; knockout gene; leukemia; leukemia treatment; methylome; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; therapeutic evaluation; tool; transcriptome; transcriptome sequencing

Project summary Mixed phenotype acute leukemia (MPAL) is a rare and aggressive leukemia with features of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). MPAL patients are treated with either AML or ALL regimens, and patient survival is significantly impacted by age. While the median survival of children with MPAL is about 139 months, the median survival of the adult patients is only 11 months. Large scale integrative genomic analyses of pediatric and adult MPAL have identified numerous genetic mutations. However, many mutations are commonly seen in both adult and pediatric MPAL, suggesting that additional unidentified factors other than genetic mutations may contribute to the poorer prognosis observed in adult patients with MPAL. Introduction of MPAL genetic mutations in mouse models rarely leads to MPAL, instead typically results in AML or ALL. As a result, it is difficult to study MPAL in vivo and understand how aging contributes to this disease. Recently, we have developed an innovative mouse model of MPAL after serial bone marrow transplantation, in which about 90% mice developed spontaneous B/myeloid MPAL, a major subtype of human MPAL. MPAL in our model is highly dependent on aging of bone marrow cells, as transplantation with young mouse bone marrow cells did not result in such a phenotype. Strikingly, we found that gene knockout of histone deacetylase Sirt1 substantially inhibited development of MPAL in our mouse model. Therefore, our preliminary studies simultaneously generated a new mouse model for B/M MPAL, and identified a novel role of Sirt1 in this malignancy. In this proposal, we will further characterize this mouse model and test the effect of targeting SIRT1 on B/M MPAL. In specific aim 1, we will characterize genome-wide mutations and epigenetic alterations in mouse B/M MPAL for comparison with adult human B/M MPAL. In specific aim 2, we will determine the effect of inhibiting Sirt1 and its metabolic pathways for hematopoietic stem cell aging on B/M MPAL in the mouse model and adult human B/M MPAL samples. Successful completion of this proposal will validate a novel mouse model of B/M MPAL for future mechanistic studies and testing therapeutic intervention, advance our understanding of aging effect on adult B/M MPAL, and identify new therapeutic targets to improve treatment of this devastating disease.

项目概要 混合表型急性白血病（MPAL）是一种罕见的侵袭性白血病，具有急性髓系白血病和急性髓系白血病的特征。 白血病（AML）和急性淋巴细胞白血病（ALL）。 MPAL 患者接受 AML 或 ALL 治疗 治疗方案和患者生存率受年龄影响显着。而患有 MPAL 的儿童的中位生存期 约为139个月，成年患者的中位生存期仅为11个月。大规模整合基因组 对儿童和成人 MPAL 的分析发现了许多基因突变。然而，许多突变 在成人和儿童 MPAL 中都很常见，这表明除了 基因突变可能导致成年 MPAL 患者预后较差。简介 小鼠模型中的 MPAL 基因突变很少导致 MPAL，而通常会导致 AML 或 ALL。作为一个 因此，很难在体内研究 MPAL 并了解衰老如何导致这种疾病。最近，我们 开发了连续骨髓移植后 MPAL 的创新小鼠模型，其中约 90% 的小鼠出现自发性 B/髓样 MPAL，这是人类 MPAL 的主要亚型。我们模型中的 MPAL 是 高度依赖于骨髓细胞的老化，正如年轻小鼠骨髓细胞移植一样 不会导致这样的表型。引人注目的是，我们发现组蛋白脱乙酰酶 Sirt1 的基因敲除显着 抑制我们的小鼠模型中 MPAL 的发育。因此，我们的前期研究同时 为 B/M MPAL 生成了一个新的小鼠模型，并确定了 Sirt1 在这种恶性肿瘤中的新作用。在这个 提案中，我们将进一步表征该小鼠模型并测试针对 B/M MPAL 的 SIRT1 效果。在 具体目标 1，我们将表征小鼠 B/M MPAL 的全基因组突变和表观遗传改变 与成人 B/M MPAL 的比较。在具体目标2中，我们将确定抑制Sirt1及其的效果 小鼠模型和成人 B/M 中 B/M MPAL 造血干细胞衰老的代谢途径 MPAL 样品。该提案的成功完成将为未来验证 B/M MPAL 的新型小鼠模型 机制研究和测试治疗干预，加深我们对衰老对成人 B/M 影响的理解 MPAL，并确定新的治疗靶点以改善这种破坏性疾病的治疗。