Pre-Clinical and Clinical Investigation of MLL-PTD Acute Myeloid Leukemia

MLL-PTD 急性髓系白血病的临床前和临床研究

• 批准号: 7715172
• 负责人: MICHAEL A CALIGIURI
• 金额: $ 27.82万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715172
• 关键词: Aberrant DNA Methylation; Acute; Acute Myelocytic Leukemia; Adult; Alleles; Apoptosis; Blast Cell; Cell Proliferation; Cells; Clinic; Clinical; Clinical Trials; DNA Methyltransferase; DNA Modification Methylases; Data; Defect; Development; Disease; Epigenetic Process; FLT3 gene; Gene Expression; Gene Mutation; Genes; Genetic; Goals; HRX protein; Hematopoiesis; Hematopoietic; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Instruction; Knock-in Mouse; Laboratories; Ligands; Lymphoid; Lysine; MLL gene; Methyltransferase; Modeling; Molecular; Mus; Mutation; Myelogenous; Outcome; Patients; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Process; Publishing; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Reporting; Research; Role; Safety; Specific qualifier value; Testing; Therapeutic; Translating; Work; base; cell type; chemotherapeutic agent; chemotherapy; chromatin remodeling; design; experience; human disease; improved; leukemia; leukemogenesis; molecular marker; mouse model; mutant; novel; novel therapeutic intervention; outcome forecast; pre-clinical; prognostic

In acute myeloid (AML) and lymphoid (ALL) leukemias, the MLL gene fuses with over 50 partner genes or can be rearranged as the result of a self-fusion creating the partial tandem duplication {MLL-PJD). We discovered the MLL-PTD and have investigated the MLL-PTD role in leukemogenesis and its prognostic impact. We were the first to report that MLL-PTD occurs more frequently in cytogenetically normal (CN)- AML and in AML with +11 and was associated with adverse prognosis. Although more recently we have shown that the outcome of MLL-PTD AML patients has improved with intensive treatment, most of them die of their disease, thereby underscoring the need for novel and more "personalized" treatment approaches. Interestingly, we observed MLL-PTD blasts from patients with dismal outcome often harbor additional adverse prognostic molecular markers, such as the FLT3 internal tandem duplication {FLT3 ITD) and that certain epigenetic aberrations are characteristically associated with the MLL-PTD. These data, therefore suggest that additional genetic and epigenetic "hits" are necessary for development of the MLL- PTD leukemia phenotype. In support of the "multiple hits" leukemogenic model, the Mil PTD as a single knocked-in defect in mice benignly alters hematopoiesis but does not induce leukemia, while it cooperates with the knocked-in Flt3 ITD defect to induce fatal AML. Reversion of epigenetic changes by hypomethylating agents and histone deacetylase inhibitors increases sensitivity of MLL PTD cells to chemotherapy. Based on these findings, therefore, we hypothesize that MLL PTD AML can be used as a model to elucidate the molecular mechanism(s) leading to multi-step leukemogenesis so that novel targeting therapies can be developed. To test our hypotheses, we collectively as a laboratory and clinical investigational team working together propose the following three aims: 1. To further characterize genetic and epigenetic mechanisms leading to MLL PTD AML using an Mil PTD/Flt3 ITD murine model; 2. To design novel therapeutic approaches targeting genetic and epigenetic aberrations in MLL PTD AML; 3. To perform an expanded Phase I clinical trial using a combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors followed by intensive chemotherapy to assess safety and efficacy in adult patients with relapsed or refractory AML, particularly in patients with the MLL PTD. Our ultimate goal is to improve outcome of MLL PTD AML patients. We anticipate, however, that some of the discoveries derived from this project will also improve our understanding and our ability to treat other subtypes of AML. RELEVANCE (See instructions): We were the first to identify a type of acute myeloid leukemia (AML) characterized by a gene mutation called MLL PTD that is associated with short survival. We have created a mouse model of MLL PTD leukemia. We will use this model to understand the mechanisms through which MLL PTD causes leukemia and test novel therapies. Our laboratory discoveries will be rapidly moved to the clinic. Our goal is to improve the outcome of patients with MLL PTD AML, but also to extend our discoveries from to other subtypes of AML.

在急性髓性白血病（AML）和淋巴性白血病（ALL）中，MLL基因与超过50个伴侣基因融合