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）：尽管在理解急性髓样白血病（AML）的遗传原因方面取得了长足进展，但化学疗法的主要疗法，Cytarabine与蒽环类药物结合使用了40多年。尽管它们的临床效用，但这些药物却遭受了相当大的毒性，而长期结果令人失望：AML患者的五年生存率少于20％。这项工作的重点是针对大约50％的急性髓样白血病（AML）病例开发更好的治疗，该病例与HOX辅助因子MEIS1一起表达了同型转录因子HOXA9。 HOXA9/MEIS1放松管制已被证明是白血病的关键，也是不良预后的重要独立标记。我们的目标是更好地定义白血病中HOX放松管制的机制，以识别可以针对治疗的关键相互作用或酶促活性。对这些靶标的放松管制的AML病例与混合谱系白血病基因MLL的重排密切相关，一种组蛋白H3赖氨酸4特异性甲基转移酶（大约涉及所有AML病例的大约10％），核酚蛋白（NPM1）的突变（NPM1），导致其重新定位的cytopalization cytoplization cytoplization cytoplization cytoplization cytoplizass（NPMC）（npmc）+（+）（+）+（npmc）+（+）（ CDX2的过表达发生在多达90％的正常核型AML病例中。最常见的MLL重排是平衡的易位，将MLL融合到许多核转运因子之一中。在其他情况下，MLL融合到易位的伴侣，该伙伴二聚截断的MLL分子。最后，由于编码氨基末端MLL的序列的重复，MLL（MLL-PTD）的部分串联重复，也放大了HOX基因表达。 NPMC+的AML病例几乎从未有MLL重排，但具有与MLL重排病例的相似表达曲线以及与FLT3突变的强大合作性，这表明这些病例具有HOX放松管制的最终共同途径。我们发现，通过与聚合酶相关的因子复合物PAFC相互作用，将MLL招募到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DOT1L靶向基因座，并且这种募集以及野生型MLL都是转化所必需的。该提案中的实验将为白血病中MLL-PAF轴或DOT1L的治疗靶向奠定基础，并具有不同的转化机制。 公共卫生相关性：急性髓样白血病（AML）的治疗与相当大的毒性有关，长期结果令人失望：AML患者的五年生存率小于20％。这项工作着重于通过专门针对调节AML细胞生存基因的机制来开发更好的AML治疗。实验大纲将确定AML亚型可能对这些新型疗法做出反应，哪些治疗靶标是进一步治疗性发育的最大希望。