Developing and credentialing patient-derived xenograft models to advance therapeutic approaches for chronic myelomonocytic leukemia

慢性粒单核细胞白血病(CMML)是一种以细胞减少为特征的致死性白血病亚型， 骨髓发育不良，单核细胞增多，以及转化为急性髓系白血病(AML)的倾向。它是 是最具侵袭性的慢性髓系恶性肿瘤之一，中位生存期为34个月。复发性 已在40多个影响染色质状态、mRNA剪接、 造血分化和细胞因子信号通路。不幸的是，尽管越来越多的人 虽然在CMML中发现了基因改变，但还没有开发出有可能改善这种疾病的治疗方法。 CMML的自然历史较差。此外，使用基因工程小鼠建立CMML模型的尝试 模型还没有概括出人类疾病独特的临床或组织学特征。 利用免疫功能低下的小鼠建立了急性白血病患者来源的异种移植(PDX) 准确模拟疾病的宿主，并已被用于证明体内假定的治疗靶点。 然而，到目前为止，针对CMML的PDX模型的开发取得的成功有限。最近，我们的 小组已经克服了这一限制，并产生了高度和遗传精度的CMML PDX模型 通过使用几个新的表达人的改良NOD/SCID IL2R空(Nsg)小鼠株 独特驱动CMML的细胞因子。此外，我们还利用这些PDX模型来确定新的治疗方法 靶向CMML特定基因亚群中异常的细胞因子信号特征和信使核糖核酸剪接。 在这项建议中，我们的目标是进一步定义这些模型对人体条件的逼真度，并测试几个 对CMML患者可立即翻译的新的临床前治疗方法如下：在目标1 我们将严格探索我们的PDX模型与各自患者的保真度，方法是确定 PDX模型概括了CMML的整个临床、转录和蛋白质组谱；Aim 2将 确定CMML PDX模型是否可以概括患者对JAK2抑制剂的特定反应 我们已完成的JAK1/2抑制剂Ruxolitinib在CMML的I/II期临床试验样本和 前瞻性2期Ruxolitinib CMML临床研究；目标3将确定Ruxolitinib CMML的疗效和机制 基于剪接体基因突变的剪接体调节化合物在CMML PDX中的作用 状态。这些研究的意义在于，它们将在遗传和表型上创造出准确的 目前缺乏临床前模型的一种侵袭性癌症的模型。此外，健康 相关的是，我们的研究将为这种缺乏任何有效的治疗方法找到新的治疗方法 目前正在进行治疗。

Chronic Myelomonocytic Leukemia (CMML) is a lethal subtype of leukemia characterized by cytopenias, marrow dysplasia, monocytosis, and a propensity for transformation to acute myeloid leukemia (AML). It is among the most aggressive chronic myeloid malignancies with a median survival of 34 months. Recurrent mutations in CMML have been identified in over 40 genes affecting chromatin state, mRNA splicing, hematopoietic differentiation, and cytokine signaling pathways. Unfortunately, despite the increasing number of genetic alterations identified in CMML, no therapies have been developed with the potential to improve the poor natural history of CMML. Moreover, attempts to model CMML using genetically engineered mouse models have not recapitulated the unique clinical or histological characteristics of the human disease. Patient-derived xenografts (PDX) of acute leukemias have been created using immunocompromised mouse hosts that accurately model the disease and have been used to credential putative therapeutic targets in vivo. However, until now, there has been limited success with development of PDX models for CMML. Recently, our groups have overcome this limitation and generated highly and genetically accurate PDX models of CMML through the use of several novel modified NOD/SCID IL2R null (NSG) mouse strains expressing human cytokines that uniquely drive CMML. Moreover, we have utilized these PDX models to identify novel therapies targeting aberrant cytokine-signaling characteristics and mRNA splicing in specific genetic subsets of CMML. In this proposal we aim to further define the fidelity of these models to the human condition and test several novel preclinical therapeutic approaches with immediate translatability to CMML patients as follows: In Aim 1 we will rigorously explore the fidelity of our PDX models compared to their respective patients by determining if PDX models recapitulate the entire clinical, transcriptional, and proteomic spectrum of CMML ; Aim 2 will determine whether CMML PDX models can recapitulate patient-specific responses to JAK2 inhibitors using samples from both our completed phase I/II clinical trial of the JAK1/2 inhibitor ruxolitinib in CMML and a prospective phase 2 ruxolitinib CMML clinical study; Aim 3 will determine the efficacy and mechanism of action of spliceosomal modulatory compounds in CMML PDXs based on spliceosomal gene mutation status. The significance of these studies is that they will create genetically and phenotypically accurate models of an aggressive form of cancer that is lacking preclinical models currently. Moreover, the health relatedness is that our studies will identify novel therapies for this condition, which lacks any effective therapies currently.