Genetic Dissection of Acute Myeloid Leukemia.

描述（由申请人提供）：AML是一种破坏性的血液肿瘤，是成人白血病中最常见的类型，也是白血病中生存率最低的疾病。在美国，每年有近45000人被确诊，目前的5年生存率只有24%，治疗后复发率接近50%。AML是一个更广泛的髓系肿瘤家族的一部分，包括多种但相关的疾病，如骨髓增生异常综合征（MDS）、骨髓增生性肿瘤（MPN）和慢性髓单细胞白血病（CMML），后者经常发展为AML。目前，包括AML在内的大多数此类疾病都没有靶向治疗方法，因此研究其诱导和进展的分子机制具有重要意义。我们最近在CMML患者中发现了新的体细胞获得性突变，使Notch信号通路失活。有趣的是，这些Notch突变不是单独发生的，而是与其他基因组“命中”共同发生的，包括TET2、ASXL1、KRAS和JAK2基因的突变。我们在此发表的初步数据表明：a) Notch通路在髓单核细胞白血病（包括AML）中被“关闭”；b)通过灭活突变和表观遗传沉默来实现该通路的抑制；c)该通路的重新激活可以抑制小鼠体内CMML和体外人AML的生长。在本应用中，我们：a)评估AML中Notch通路再激活的生物学效应，b)确定人类AML中通路抑制的分子和表观遗传模式，以及c)研究Notch通路突变与其他基因组病变的合作及其在AML发生和进展中的作用。我们坚信，这些研究可以引导未来AML和相关髓系肿瘤的靶向治疗，因为Notch通路的再激活可以使用肽和抗体激动剂方法来实现。

DESCRIPTION (provided by applicant): AML is a devastating blood tumor, the most common type of leukemia in adults, a disease that continues to have the lowest survival rate within leukemia. Nearly 45,000 people are diagnosed each year in the US, and the current 5-year survival frequency is only 24% with an almost 50% relapse rate after treatment. AML is a part of a wider family of myeloid neoplasms that include diverse but related diseases like myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), a disease that frequently develops into AML. Currently, there are no targeted therapies for most of these diseases, including AML, making the study of the molecular mechanisms of their induction and progression of great significance. We have recently identified novel somatically acquired mutations inactivating the Notch signaling pathway in patients with CMML. Interestingly, these Notch mutations do not act in isolation but they co-occur with additional genomic "hits", including mutations on the TET2, ASXL1, KRAS and JAK2 genes. Our published and preliminary data presented here demonstrate that: a) The Notch pathway is "switched-off" in myelo-monocytic leukemias, including AML, b) Inhibition of the pathway is achieved both by inactivating mutations and epigenetic silencing, c) Re-activation of the pathway can inhibit the growth of mouse CMML in vivo and human AML in vitro. In this application we: a) Assess the biological effects of Notch pathway re- activation in AML, b) Identify the molecular and epigenetic mode of pathway inhibition in human AML and c) Study co-operation of Notch pathway mutations with additional genomic lesions and their effect in AML initiation and progression. We strongly believe that these studies can lead to future targeted therapies of AML and related myeloid neoplasms, as re-activation of the Notch pathway can be achieved using both peptide and antibody agonist approaches.