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.

项目摘要 混合表型急性白血病（MPAL）是一种罕见而侵略性的白血病，具有急性髓样的特征 白血病（AML）和急性淋巴细胞白血病（全部）。 MPAL患者用AML或全部治疗 治疗疗法和患者的生存受年龄的显着影响。而儿童的中位生存 大约为139个月，成年患者的中位存活率仅为11个月。大规模综合基因组 小儿和成人MPAL的分析已经确定了许多遗传突变。但是，许多突变 通常在成人和小儿MPAL中都可以看出，这表明除了 基因突变可能导致成人MPAL患者观察到的较差的预后。引入 小鼠模型中的MPAL遗传突变很少导致MPAL，而是导致AML或全部导致。作为 结果，很难在体内研究MPAL并了解衰老如何对这种疾病有何贡献。最近，我们 在串行骨髓移植后开发了MPAL的创新小鼠模型，其中大约 90％的小鼠出现了自发的B/髓样MPAL，这是人类MPAL的主要亚型。我们模型中的MPAL是 高度依赖骨髓细胞的衰老，因为对年轻小鼠骨髓细胞的移植确实 不会导致这种表型。引人注目的是，我们发现组蛋白脱乙酰基酶SIRT1的基因敲除基因敲除 在我们的小鼠模型中抑制MPAL的发展。因此，我们的初步研究同时 为B/M MPAL生成了新的小鼠模型，并确定了SIRT1在这种恶性肿瘤中的新作用。在这个 提案，我们将进一步表征该小鼠模型，并测试靶向SIRT1对B/M MPAL的影响。在 具体的目标1，我们将表征全基因组突变和小鼠B/M MPAL的表观遗传改变 与成人人类B/M MPAL进行比较。在特定目标2中，我们将确定抑制SIRT1及其的影响 小鼠模型中B/M MPAL上造血干细胞老化的代谢途径和成年人B/M MPAL样品。该提案的成功完成将验证B/M MPAL的新型鼠标模型 机械研究和测试治疗干预措施，提高我们对衰老对成人B/M的影响 MPAL，并确定新的治疗靶标，以改善对这种毁灭性疾病的治疗。