Genomic profiling and development of murine models of transformation of MPNs

描述(申请人提供)：费城染色体阴性的骨髓增生性肿瘤(MPN)是克隆性造血干细胞疾病，包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)。MPN有发病和死亡的风险。然而，重要的是，相当大比例的PV、ET或PMF患者发展为急性髓系白血病(AML)。这种进展往往是致命的，中位生存期不到4个月。可用于AML的标准治疗已被证明对这些患者的预后影响很小或没有影响。因此，迫切需要开发新的治疗方法。利用靶基因分析，我们已经开始对MPN后AML进行基因组学评估。我们的初步数据表明，在白血病转化(LT)时发现的突变不同于新发AML中常见的突变。这一数据表明，MPN后AML在基因上与新生AML不同，需要更广泛的努力来进一步定义MPN后AML的突变谱。我们已经建立了第一个报道的MPN后AML的遗传学准确的小鼠模型。我们对这一初始模型进行了详细的分析。此外，利用这个模型，我们已经开始在体内和体外测试新的治疗策略。我们试图进一步了解MPN向AML发展过程中涉及的遗传事件。这些信息将被用来开发新的从基因上准确的急性髓细胞白血病进展的临床前模型。然后，我们计划使用这些模型来测试新的治疗策略。利用我们将从这些努力中获得的遗传学和生物学见解，我们寻求最终将这些发现转化为这种毁灭性疾病的新治疗策略。这些研究 将由Raajit Rampal博士领导，他是纪念斯隆-凯特琳癌症中心的初级教员，由Ross Levine博士指导。莱文博士是白血病研究领域的领导者，在有效、快速地指导前受训人员实现独立方面有着良好的记录。纪念斯隆-凯特琳癌症中心和查尔斯·索耶斯博士领导的人类肿瘤学和病理学项目为培养转化型癌症研究的发展事业提供了一个特殊的环境。为了实现成为一名独立研究员的长期目标，拉姆帕尔博士制定了一套结构化的活动课程，旨在扩大她的知识基础、扩大技术储备和培养领导技能，并组建了一个由顶尖科学家组成的咨询委员会。

DESCRIPTION (provided by applicant): The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, which include Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF)). MPNs carry a risk of morbidity and mortality. Importantly, however, a substantial proportion of patients with PV, ET or PMF develop transformation to acute myeloid leukemia (AML). This progression is often fatal, with a median survival of less than four months. Standard treatments available for AML have proven to have little or no impact on outcome in these patients. Thus, there is a pressing need to develop new treatments. Using target gene analysis, we have begun genomic assessment of post- MPN AML. Our preliminary data demonstrates that the mutations found at the time of leukemic transformation (LT) differs from those commonly found in de novo AML. This data suggests that post-MPN AML is genetically distinct from de novo AML, and that more expansive efforts are required to further define the spectrum of mutations in post-MPN AML. We have developed the first reported genetically accurate murine model of post-MPN AML. We have performed detailed analysis of this initial model. Further, using this model, we have begun testing new therapeutic strategies in vivo and in vitro. We seek to further understand the genetic events that are involved in the progression of MPN to AML. This information will then be used to develop new genetically accurate pre-clinical models of progression to AML. We then plan to use these models to test new therapeutic strategies. Using the genetic and biological insights we will gain from these efforts, we seek to ultimately translate these findings into new therapeutic strategies for this devastating disease. The studies will be led by Dr. Raajit Rampal, a junior faculty member at Memorial Sloan-Kettering Cancer Center under the mentorship of Dr. Ross Levine. Dr. Levine is a leader in leukemia research with an established track record of effectively, rapidly mentoring former trainees into independence. The Memorial Sloan-Kettering Cancer Center, and the Human Oncology and Pathogenesis program, led by Dr. Charles Sawyers, offers an exceptional environment for cultivating a developing career in translational cancer research. To achieve his long-term goal of becoming an independent investigator Dr. Rampal has developed a structured curriculum of activities aimed at broadening her knowledge base, expanding technical repertoire and developing leadership skills, and has assembled an advisory committee of leading scientists.