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: 10435355
• 负责人: WENYONG CHEN
• 金额: $ 25.2万
• 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/10435355
• 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; Lead; 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; Stem Cell Development; Testing; Therapeutic; Therapeutic Intervention; Transcript; Transplantation; age effect; age related; bisulfite sequencing; cell growth; disease mechanisms study; exome sequencing; genome-wide; 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）是一种罕见的侵袭性白血病， 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，患者生存率受到年龄的显着影响。MPAL患儿的中位生存率 大约是139个月，成年患者的中位生存期只有11个月。大规模整合基因组 对儿童和成人MPAL的分析已经鉴定出许多基因突变。然而，许多突变 在成人和儿童MPAL中常见，这表明除了 基因突变可能导致MPAL成人患者的预后较差。引入 小鼠模型中的MPAL基因突变很少导致MPAL，而是通常导致AML或ALL。作为 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 已经开发了一种创新的MPAL小鼠模型，在连续骨髓移植后， 90%的小鼠发生自发性B/髓样MPAL，这是人MPAL的主要亚型。在我们的模型中，MPAL是 高度依赖于骨髓细胞的老化，就像年轻小鼠骨髓细胞移植一样 不会导致这种表型。引人注目的是，我们发现组蛋白去乙酰化酶Sirt 1的基因敲除基本上 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 建立了一种新的B/M MPAL小鼠模型，并确定了Sirt 1在这种恶性肿瘤中的新作用。在这 根据该提议，我们将进一步表征该小鼠模型并测试靶向SIRT 1对B/M MPAL的影响。在 具体目标1，我们将表征小鼠B/M MPAL中全基因组突变和表观遗传学改变， 与成人B/M MPAL的比较。在具体目标2中，我们将确定抑制Sirt 1的效果及其对细胞的影响。 小鼠模型和成人B/M中造血干细胞老化对B/M MPAL的代谢途径 MPAL样品。成功完成这一建议将验证一个新的小鼠模型的B/M MPAL的未来 机制研究和测试治疗干预，提高我们对成人B/M老化效应的认识 MPAL，并确定新的治疗靶点，以改善这种毁灭性疾病的治疗。