New Therapeutic Targets in AML

AML 的新治疗靶点

• 批准号: 8105707
• 负责人: Jay L. Hess
• 金额: $ 34.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105707
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Anthracyclines; CDX2 gene; Cells; Chemicals; Chimeric Proteins; Clinical; Complex; Cytarabine; Cytoplasm; DNA Polymerase II; DNA Sequence Rearrangement; Development; Dimerization; Equilibrium; FLT3 gene; Gene Expression; Genes; Genetic; Goals; HOXA9 gene; Hematopoietic; Histone H3; Homeobox; Homeobox Genes; Karyotype; Knockout Mice; Laboratories; Leukemic Cell; Lysine; MEIS1 gene; MLL gene; Malignant Neoplasms; Methyltransferase; Michigan; Molecular Profiling; Morbidity - disease rate; Mutation; Myeloid Leukemia; Myeloid-Lymphoid Leukemia Protein; NPM1 gene; NUP98 gene; Nuclear; Nuclear Translocation; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Polymerase; Proteins; Recruitment Activity; Regulation; Survival Rate; Toxic effect; Transcription Coactivator; Universities; Up-Regulation; Work; cell growth; chemotherapy; cofactor; in vivo; inhibitor/antagonist; insight; leukemia; leukemogenesis; new therapeutic target; novel; nucleophosmin; outcome forecast; overexpression; programs; research study; small molecule; therapeutic development; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Although considerable progress has been made in understanding the genetic causes of acute myeloid leukemia (AML), the mainstay of chemotherapy, cytarabine in combination with anthracyclines, have been in use for more than 40 years. Despite their clinical utility, the drugs suffer from considerable toxicity and the long-term results are disappointing: the five-year survival rate for AML patients is less than 20%. The focus of this work is on developing better therapy for the approximately 50% of acute myeloid leukemia (AML) cases that over express the homeobox transcription factor HOXA9, along with the HOX cofactor MEIS1. HOXA9/MEIS1 deregulation has been shown to be pivotal for leukemogenesis as well as an important independent marker for adverse prognosis. Our goal is to better define mechanisms of HOX deregulation in leukemia in order to identify critical interactions or enzymatic activities that could be targeted therapeutically. AML cases with deregulation of these targets are strongly associated with rearrangement of the mixed lineage leukemia gene MLL, a histone H3 lysine 4 specific methyltransferase (involved in approximately 10% of all AML cases), mutation of nucleophosmin (NPM1), resulting in its re-localization to the cytoplasm (NPMc+)(approximately 35% of AML cases) or overexpression of CDX2, which occurs in as many as 90% of normal karyotype AML cases. The most common MLL rearrangements are balanced translocations that fuse MLL to one of a number of nuclear translocation factors. In other cases, MLL is fused to translocation partners that dimerize the truncated MLL molecule. Finally, partial tandem duplication of MLL (MLL-PTD), as a result of duplication of sequences encoding the amino terminal MLL, also deregulate HOX gene expression. AML cases with NPMc+ almost never have MLL rearrangements, but share similar expression profiles as MLL rearranged cases as well as strong cooperativity with FLT3 mutations suggesting these cases share final common pathways for HOX deregulation. We discovered that MLL is recruited to HOX loci through interaction with the polymerase associated factor complex, PAFc, where it regulates HOX gene expression through its histone H3 lysine 4 methyltransferase activity. In addition, we and others have found that common MLL fusion proteins recruit the histone H3 lysine 79 methyltransferase DOT1L to target loci and that this recruitment, along with wild type MLL, are all required for transformation. The experiments in this proposal will lay the groundwork for therapeutic targeting of the MLL-PAF axis or DOT1L in leukemias with varying mechanisms of transformation.) PUBLIC HEALTH RELEVANCE: Therapy for acute myeloid leukemia (AML) is associated with considerable toxicity and the long-term results are disappointing: the five-year survival rate for AML patients is less than 20%. This work focuses on developing better therapy for AML by specifically targeting mechanisms that regulate genes required for the survival of AML cells. The experiments outline will identify what AML subtypes are likely to respond to these novel therapies and which therapeutic targets hold the greatest promise for further therapeutic development.

描述（由申请人提供）：尽管在了解急性髓性白血病（AML）的遗传原因方面取得了相当大的进展，但化疗的主要药物阿糖胞苷与蒽环类药物联合使用已超过40年。尽管它们具有临床实用性，但这些药物具有相当大的毒性，长期结果令人失望：AML患者的五年生存率不到20%。这项工作的重点是为大约50%的急性髓性白血病（AML）病例开发更好的治疗方法，这些病例过表达同源框转录因子HOXA 9，沿着HOX辅因子MEIS 1。HOXA 9/MEIS 1失调已被证明是白血病发生的关键以及不良预后的重要独立标志物。我们的目标是更好地定义白血病中HOX失调的机制，以确定可用于治疗的关键相互作用或酶活性。这些靶点失调的AML病例与混合系白血病基因MLL重排密切相关，MLL是一种组蛋白H3赖氨酸4特异性甲基转移酶（涉及约10%的所有AML病例），核磷蛋白（NPM 1）突变，导致其重新定位于细胞质（NPMc+）（大约35%的AML病例）或CDX 2过表达，其发生在多达90%的正常核型AML病例中。最常见的MLL重排是将MLL融合到许多核易位因子之一的平衡易位。在其他情况下，MLL与使截短的MLL分子二聚化的易位配偶体融合。最后，MLL的部分串联重复（MLL-PTD），作为编码氨基末端MLL的序列重复的结果，也使HOX基因表达失调。具有NPMc+的AML病例几乎从未发生MLL重排，但与MLL重排病例具有相似的表达谱以及与FLT 3突变的强协同性，表明这些病例具有HOX失调的最终共同途径。我们发现MLL通过与聚合酶相关因子复合物PAFc相互作用被募集到HOX基因座，在那里它通过其组蛋白H3赖氨酸4甲基转移酶活性调节HOX基因表达。此外，我们和其他人已经发现，常见的MLL融合蛋白募集组蛋白H3赖氨酸79甲基转移酶DOT 1 L到靶基因座，并且这种募集，沿着野生型MLL，都是转化所需的。该提案中的实验将为具有不同转化机制的白血病中MLL-PAF轴或DOT 1 L的治疗靶向奠定基础。 公共卫生相关性：急性髓细胞白血病（AML）的治疗与相当大的毒性有关，长期结果令人失望：AML患者的五年生存率低于20%。这项工作的重点是通过特异性靶向调节AML细胞生存所需基因的机制来开发更好的AML治疗方法。实验概述将确定哪些AML亚型可能对这些新疗法产生反应，以及哪些治疗靶点对进一步的治疗开发具有最大的希望。