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

在急性髓系(AML)和淋巴样(ALL)白血病中，MLL基因与50多个配对基因或 可以作为自融合产生部分串联复制的结果进行重排(MLL-PJD)。我们 发现了MLL-PTD，并研究了MLL-PTD在白血病发生及其预后中的作用 冲击力。我们首次报道MLL-PTD在细胞遗传学正常(CN)中更常见。 AML和+11的AML患者预后不良。尽管最近我们有了 显示MLL-PTD AML患者经过强化治疗后预后有所改善，其中大多数 他们死于疾病，从而强调了对新的和更“个性化”治疗的需要 接近了。有趣的是，我们观察到来自预后不佳患者的MLL-PTD细胞。 其他不利预后的分子标志物，如Flt3内部串联复制(Flt3ITD) 某些表观遗传学异常与MLL-PTD特征相关。这些数据， 因此，提示额外的遗传和表观遗传的“命中”对于MLL的发展是必要的- PTD白血病表型。为支持“多次命中”的白血病模型，Mil PTD作为单一的 小鼠的敲入缺陷有益于改变造血，但不会诱发白血病，但它是协同作用的 与敲入的Flt3 ITD缺陷导致致死性AML。表观遗传改变的逆转 去甲基化药物和组蛋白脱乙酰酶抑制剂增加MLL PTD细胞对 化疗。因此，基于这些发现，我们假设MLL PTD AML可以用作 模型阐明导致多步白血病发生的分子机制(S)让新奇 靶向疗法可以被开发出来。为了验证我们的假设，我们集体作为实验室和临床 研究小组共同提出了以下三个目标：1.进一步研究基因 以及利用Mil PTD/Flt3 ITD小鼠模型导致MLL PTD AML的表观遗传学机制； 设计针对MLL PTD AML的遗传和表观遗传学异常的新的治疗方法； 使用DNA甲基转移酶(DNMT)和联合应用进行扩大的I期临床试验 组蛋白脱乙酰酶(HDAC)抑制剂在强化化疗后的安全性和有效性评价 复发或难治性AML的成人患者，特别是MLL PTD患者。我们的终极目标 是为了改善MLL PTD AML患者的预后。然而，我们预计，一些发现 从这个项目衍生出来的也将提高我们对AML其他亚型的理解和治疗能力。 相关性(请参阅说明)： 我们首次发现了一种以基因突变为特征的急性髓系白血病(AML) 称为MLL PTD，与短期存活有关。我们已经建立了MLL PTD的小鼠模型 白血病。我们将使用这个模型来理解MLL PTD导致白血病的机制 并测试新的疗法。我们的实验室发现将很快被转移到临床上。我们的目标是 改善MLL PTD AML患者的预后，同时也将我们的发现从 急性髓系白血病的亚型。

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.