Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

慢性粒单核细胞白血病 (CMML) 的分子和细胞机制

• 批准号: 10657244
• 负责人: Jing Zhang
• 金额: $ 40.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657244
• 关键词: Acceleration; Acute Myelocytic Leukemia; Affect; Animal Model; Binding; Biological Assay; Bromodomain; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chronic Myelomonocytic Leukemia; Collaborations; Coupled; Diagnosis; Disease; Down-Regulation; Elderly; Enhancers; Exhibits; Flow Cytometry; Funding; Genetic; Genetic Transcription; Hematopoietic stem cells; Histones; Human; Immune; Immunotherapeutic agent; In Vitro; International; Lead; Leukemic Cell; Ligands; Link; MEK inhibition; MEKs; Malignant Neoplasms; Mediating; Membrane Proteins; Molecular; Mus; Mutation; Oncogenic; Outcome; Pathway interactions; Patients; Phenotype; Population; Prognosis; Protein Analysis; RNA; Resolution; Sampling; Secondary acute myeloid leukemia; Signal Transduction; Sorting; T-Lymphocyte; Technology; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Effect; Transcription Factor AP-1; Transcriptional Activation; Transplantation; Up-Regulation; antileukemic activity; cell growth; cytotoxicity; effective therapy; epigenomics; exhaust; human data; immune checkpoint; immune modulating agents; improved; in vivo; inhibitor; lenalidomide; leukemia; leukemic transformation; mouse model; novel; novel therapeutics; overexpression; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; receptor; small hairpin RNA; transcriptome sequencing; transcriptomics; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Chronic myelomonocytic leukemia (CMML) is a devastating cancer with an urgent and unmet need for effective therapies (median survival: ~28 months). Approximately 30% of CMML cases evolve to acute myeloid leukemia (AML) soon after their initial diagnosis, contributing to the poor prognosis of CMML patients. During the prior funding period, we collaborated with the International MDS/MPN Consortium and demonstrated that concurrent NRAS and ASXL1 mutations define a population of CMML patients with shorter leukemia-free survival than those with ASXL1 mutations only. Based on our human data, we characterized NrasG12D/+; Asxl1-/- (NA) mice that model CMML patients with concurrent NRAS and ASXL1 mutations. NA mice developed CMML with accelerated progression and in ~50% of these mice CMML transformed to AML (secondary AML, sAML). NA leukemia cells exhibited hyperactivation of MEK/ERK signaling and increased global level of H3K27Ac, a histone mark bound by bromodomain and extra-terminal domain (BET) proteins for gene transcriptional activation. Upregulation of AP-1 transcription factors (TFs) mediated the overexpression of PD-L1 and CD86, two inhibitory immune checkpoint ligands, and helped establish a suppressive immune microenvironment in NA-sAML recipients. Combined inhibition of MEK and pan-BET proteins led to downregulation of AP-1 TF expression, partial mitigation of the suppressive immune microenvironment, enhancement of CD8 T cell cytotoxicity, and prolonged survival in NA-sAML mice. Based on our preliminary results, we hypothesize that Asxl1-/- and oncogenic Nras cooperate to accelerate CMML and promote its transformation to AML via reprogramming the immune microenvironment, which includes but may not limit to T cells. Moreover, immunomodulatory agents may further improve the therapeutic benefits of combine MEK and BET inhibition through establishing durable anti-leukemia activities in immune cells. In this renewal application, we propose the following two aims to test our hypothesis: 1) To identify the molecular and cellular mechanisms underlying the dysregulation of immune microenvironment in in NA mice; and 2) determine whether immunomodulatory agents further improve the therapeutic effects of combined MEK and BET inhibition in NA mice. Together, our proposed studies will not only provide fundamental perspectives on disease mechanisms but also test hypotheses that could potentially lead directly to potent and efficacious novel therapies for treating CMML and transformed AML.

项目总结/摘要 慢性粒单核细胞白血病（CMML）是一种毁灭性的癌症，迫切需要有效的治疗， 治疗（中位生存期：~28个月）。大约30%的CMML病例演变为急性髓细胞白血病 (AML)在最初诊断后不久，CMML患者的预后较差。前一 在资助期间，我们与国际MDS/MPN联盟合作，并证明了同时 NRAS和ASXL1突变定义了CMML患者人群，其无白血病生存期短于 只有ASXL1突变。基于我们的人类数据，我们表征了NrasG12D/+; Asxl1-/-（NA）小鼠， 伴有NRAS和ASXL1并发突变的CMML患者。NA小鼠发生CMML， 这些小鼠中约50%的CMML转化为AML（继发性AML，sAML）。NA白血病细胞 表现出MEK/ERK信号转导的过度激活和H3K27Ac的整体水平增加，H3K27Ac是一种组蛋白标记结合的蛋白。 通过布罗莫结构域和末端外结构域（BET）蛋白进行基因转录激活。的上调 AP-1转录因子（TF）介导PD-L1和CD86的过度表达，这两种抑制性免疫反应的因子是PD-L1和CD86。 检查点配体，并帮助在NA-sAML接受者中建立抑制性免疫微环境。 MEK和泛BET蛋白的联合抑制导致AP-1 TF表达下调，部分 缓解抑制性免疫微环境，增强CD8 T细胞的细胞毒性，并延长 NA-sAML小鼠的存活率。基于我们的初步结果，我们假设Asxl1-/-和致癌Nras基因可能与肿瘤的发生有关。 合作加速CMML并通过重编程免疫系统促进其向AML转化 在一些实施方案中，微环境包括但不限于T细胞。此外，免疫调节剂可进一步 通过建立持久的抗白血病药物来提高联合收割机MEK和BET抑制的治疗效果 免疫细胞的活动。在本更新申请中，我们提出以下两个目标来检验我们的假设： 1)确定免疫微环境失调的分子和细胞机制 在NA小鼠中;和2）确定免疫调节剂是否进一步改善免疫调节剂的治疗效果。 联合MEK和BET抑制NA小鼠。总之，我们提出的研究不仅将提供基本的 疾病机制的观点，而且还测试可能直接导致有效和 用于治疗CMML和转化的AML的有效的新疗法。