New Therapeutic Targets in AML

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，但主要的化疗药物阿糖胞苷联合蒽环类药物已经使用了40多年。尽管这些药物具有临床用途，但它们具有相当大的毒性，长期结果令人失望：AML患者的5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，这些病例过度表达同源盒转录因子HOXA9和HOX辅助因子MEIS1。HOXA9/MEIS1失调已被证明是白血病发生的关键因素，也是不良预后的重要独立标志物。我们的目标是更好地定义HOX在白血病中解除管制的机制，以便确定可能靶向治疗的关键相互作用或酶活性。这些靶点失调的AML病例与混合谱系白血病基因MLL的重排、组蛋白H3赖氨酸4特异性甲基转移酶（约占所有AML病例的10%）、核磷蛋白（NPM1）突变(导致其重新定位到细胞质（NPMc+）（约占AML病例的35%）或CDX2的过表达（在多达90%的正常核型AML病例中发生）密切相关。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被融合到使截断的MLL分子二聚化的易位伴侣。最后，由于编码氨基末端MLL序列的重复，MLL的部分串联重复（MLL- ptd）也会解除对HOX基因表达的调节。NPMc+的AML病例几乎从不发生MLL重排，但与MLL重排病例具有相似的表达谱，并且与FLT3突变具有很强的协同性，这表明这些病例具有HOX解除管制的最终共同途径。我们发现MLL通过与聚合酶相关因子复合物（PAFc）的相互作用被招募到HOX位点，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基因的表达。此外，我们和其他人发现，常见的MLL融合蛋白将组蛋白H3赖氨酸79甲基转移酶DOT1L招募到靶位点，并且这种招募以及野生型MLL都是转化所必需的。本提案中的实验将为MLL-PAF轴或DOT1L在不同转化机制的白血病中的治疗靶向奠定基础。

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.