Acute myeloid leukemia (AML) Research Project

总结 急性髓系白血病（acute myeloid leukemia，AML）是目前研究最多的恶性肿瘤之一。近年来 在确定AML的分子发病机制和引入新的 治疗但三年存活率仍低于50%，表明治疗进展失败 治疗疾病在某种程度上，我们认为这反映了未能充分使用基因定义的PDX模型 开发针对分子定义的疾病亚群的新疗法。如下文所述，虽然 AML的总体遗传学是复杂的，我们和其他人发现AML中存在显性癌基因， 并且靶向这些癌基因可以诱导治疗反应，尽管不能治愈。这方面的例子 方法包括使用FLT3抑制剂治疗新发和复发性FLT3 ITD突变型AML， IDH1和IDH2抑制剂。在每一种情况下，目前的治疗包括选择靶向治疗 它们是有活性的，但不是治疗性的。这可能反映了多变量的分子发病机制。推进 在这一领域，我们收集了数千个独立的AML集合，并对数十个PDX模型进行了表征。 急性髓细胞白血病这些模型已被广泛用于基础生物学的研究，但在这里，我们建议推进 使用AML PDX建模进行治疗开发。在取得进展方面有几个障碍。一是 未广泛获得和充分表征的由遗传改变定义的AML PDX模型。为了解决这个 考虑到这一点，我们选择将AML分为7个亚组，这些亚组由显性癌基因定义，正如最近所做的那样， NIH骨髓匹配研究。白血病将根据FLT3、DNMT3A、NPM1c、 IDH1、IDH2、TP53或KMT2A融合蛋白（FP）。在这里，我们将描述三种AML的异种移植 这七个亚组中的每一个的模型，并具体表征AML连续移植的生物学特征， 在NSG小鼠品系中。35例中的33例已完成植入的初步记录 样品在SA2中，我们将重点关注XP2研究的性能，以指导正在进行的临床工作。两个这样 亚组由涉及KMT 2A（先前的混合谱系白血病）的融合蛋白的存在来定义 或MLL）或核磷酸蛋白（NPM）突变（其引起蛋白质的胞质重定位）（NPMc）。两 这些AML亚型需要menin，menin是一种发病机制的表观遗传辅助调节因子， 在临床前模型中对Menin抑制的突变的响应。Menin抑制剂目前处于1期， 2期人体研究和早期结果表明，这些药物与AML的其他靶向治疗一样， 活性但不具有治疗作用。最近的研究结果表明，AML样品的分化增强， KMT2A融合蛋白（FP）可以通过将Menin抑制剂与KAT6A抑制剂组合来实现。这里我们 将使用我们表征的KMT2A FP和NPMc突变AML PDX模型来研究靶向的体内效应。 这两种蛋白质都存在于基因定义的AML亚群中。

Summary Acute myeloid leukemia (AML) is one of the most intensely studied of human malignancies. In recent years there have been major advances in defining the molecular pathogenesis of AML and introduction of new therapies. But the three-year survival rate remains below 50% indicating failures to make therapeutic advances for the disease. In part, we believe that this reflects a failure to adequately use genetically defined PDX models to develop new therapies targeted at molecularly defined subsets of the disease. As discussed below, although the overall genetics of AML is complex, we and others have found that there are dominant oncogenes in AML and that targeting of these oncogenes can induce therapeutic responses although not cures. Examples of this approach include the use of FLT3 inhibitors for de novo and relapsed FLT3 ITD mutant AML and development of IDH1 and IDH2 inhibitors. In each of these cases, current therapy includes a choice of targeted therapies which are active but not curative. This likely reflects the multi-variate molecular pathogenesis. To advance the field, we have collected thousands of independent AML collections and characterized dozens of PDX models of AML. These models have been widely used for studies of basic biology but here we propose to advance the use of AML PDX modeling for therapy development. There are several obstacles to progress. First, there are not widely available and well characterized AML PDX models defined by genetic alterations. To address this concern, we have chosen to separate AML into 7 subsets defined by dominant oncogenes as recently done by the NIH MyeloMatch study. Leukemia’s will be sub-classified based on mutations in FLT3, DNMT3A, NPM1c, IDH1, IDH2, TP53 or KMT2A fusion protein (FP). Here we will characterize xenotransplantation of three AML models for each of these seven sub-groups and specifically characterize the biology of serial transplant of AML in the NSG mouse strain. Initial documentation of engraftment has already been completed for 33 of the 35 samples. In SA2, we will focus on performance of an XP2 study to direct ongoing clinical efforts. Two of these sub-groups are defined by the presence of fusion proteins involving KMT2A (previously mixed lineage leukemia or MLL) or Nucleophosmin (NPM) mutations (that cause cytosolic re-localization of the protein) (NPMc). Both of these sub-types of AML require menin, an epigenetic co-regulator for pathogenesis and AML’s with either class of mutations responding in pre-clinical models to Menin inhibition. Menin inhibitors are currently in Phase 1 and Phase 2 human studies and early results suggest that these drugs, like other targeted therapies in AML, are active but not curative. Recent results have suggested that enhanced differentiation of AML samples containing KMT2A fusion proteins (FP) can be achieved by combining a Menin inhibitor with a KAT6A inhibitor. Here we will use our characterized KMT2A FP and NPMc mutant AML PDX models to study the effect in vivo of targeting both proteins in genetically defined subsets of AML.