Targeting HMGA1-Mediated Progression and Immune Evasion in Myeloproliferative Diseases

我建议阐明高迁移率族A1(HMGA1)染色质调节因子的调节机制 在骨髓增生性肿瘤(MPN)的疾病进展中。MPN是由以下原因引起的血液疾病 导致克隆性扩增的造血干细胞和祖细胞(HSPC)突变。具有以下特征的个人 MPN转化为骨髓纤维化(骨髓纤维化或MF)和白血病的风险增加，两者都是 其中一些与不良的临床结果有关。然而，潜在的进展机制仍然存在。 人们对此知之甚少。引起MPN的最常见的遗传损伤是Janus Kinase 2(JAK2)的突变，即 造血生长因子受体专性酪氨酸激酶。这种突变(表示为JAK2V617F)导致 增强信号转导和转录激活因子(STAT3)的磷酸化，导致 不受控制的血细胞生产。重要的是，抑制JAK/STAT信号可以改善症状 而不是阻止进步。在这里，我重点介绍HMGA1作为JAK/STAT信号在MPN进展中的关键中介。 我们关于HMGA1促进MPN进展的科学假设基于以下令人信服的假设 初步结果：1)HMGA1是一种染色质调节剂，它能打开染色质，诱导STAT3和其他 与人类血细胞前体细胞克隆扩增有关的基因。2)在MPN中阻断JAK/STAT信令 细胞减少HMGA1，表明JAK/STAT信号诱导HMGA1，HMGA1前馈 放大STAT3信号。3)HMGA1过表达导致小鼠造血祖细胞克隆性扩增， 随着年龄的增长会演变成白血病。4)HMGA1缺乏可减轻JAK2V617F MPN小鼠的病情进展。 5)在人JAK2V617F突变的MPN细胞中，HMGA1是增殖、克隆形成和白血病所必需的 在小鼠体内植入。6)HMGA1在MPN进展为MF或白血病的HSPC中升高。7)HMGA1 基于RNA调控MPN细胞周期进程和免疫逃避的基因网络 测序结果。8)HMGA1还与与异常生长和免疫相关的基因网络有关 实体瘤和其他血液病肿瘤中的逃逸。总之，这些耐人寻味的结果支持了 以下假设：1)HMGA1与STAT3合作促进克隆扩增、免疫逃避和 MPN进展，2)HMGA1通过参与增殖和免疫的基因网络驱动进展 功能，3)靶向HMGA1和STAT3将防止克隆扩张、免疫逃避和MPN进展。 目标/方法：为了测试这一点，我们提出了以下具体目标：1)确定HMGA1和HMGA1 STAT3生成前馈循环以促进MPN进展，2)确定HMGA1如何改变 MPN的免疫反应，3)开始测试同时靶向HMGA1和STAT3的治疗效果 防止异常克隆扩张、免疫逃避和MPN进展。 影响：我们期望阐明在MPN中诱导HMGA1及其下游通路的机制。这部作品 也应该揭示治疗甚至防止MPN患者进展的新方法。

I propose to elucidate mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin regulators in disease progression in myeloproliferative neoplasms (MPN). MPN are blood diseases caused by mutations in hematopoietic stem and progenitor cells (HSPC) which lead to clonal expansion. Individuals with MPN are at increased risk for transformation to bone marrow fibrosis (myelofibrosis or MF) and leukemia, both of which are associated with poor clinical outcomes. However, mechanisms underlying progression remain poorly understood. The most common genetic lesion causing MPN is a mutation in Janus Kinase 2 (JAK2), the obligate tyrosine kinase of hematopoietic growth factor receptors. This mutation (denoted JAK2V617F) causes enhanced phosphorylation of the Signal Transducer and Activator of Transcription (STAT3), resulting in uncontrolled production of blood cells. Importantly, inhibiting JAK/STAT signaling improves symptoms but does not prevent progression. Here, I focus on HMGA1 as a key mediator of JAK/STAT signaling in MPN progression. Our scientific premise that HMGA1 fosters progression in MPN is based on the following compelling preliminary results: 1) HMGA1 is a chromatin regulator that “opens” chromatin to induce STAT3 and other genes involved in clonal expansion in human blood cell progenitors. 2) Blocking JAK/STAT signaling in MPN cells decreases HMGA1, suggesting that JAK/STAT signals induce HMGA1, and HMGA1 feeds forward to amplify STAT3 signals. 3) Hmga1 overexpression causes clonal expansion in mouse blood cell progenitors, which evolves to leukemia with aging. 4) Hmga1 deficiency mitigates progression in mice with JAK2V617F MPN. 5) In human JAK2V617F mutant MPN cells, HMGA1 is required for proliferation, clonogenicity, and leukemia engraftment in mice. 6) HMGA1 increases in human HSPC with MPN progression to MF or leukemia. 7) HMGA1 regulates gene networks involved in cell cycle progression and immune evasion in MPN based on RNA sequencing results. 8) HMGA1 is also linked to gene networks associated with abnormal growth and immune evasion in solid tumors and other hematologic cancers. Together, these intriguing results support the following hypotheses: 1) HMGA1 cooperates with STAT3 to foster clonal expansion, immune evasion, and MPN progression, 2) HMGA1 drives progression through gene networks involved in proliferation and immune function, 3) Targeting HMGA1 and STAT3 will prevent clonal expansion, immune evasion, and MPN progression. Aims/Approach: To test this, we propose the following Specific Aims: 1) To determine whether HMGA1 and STAT3 generate a feed-forward loop to promote MPN progression, 2) To determine how HMGA1 alters the immune response in MPN, 3) To begin to test the therapeutic efficacy of targeting both HMGA1 and STAT3 to prevent aberrant clonal expansion, immune evasion, and MPN progression. Impact: We expect to elucidate mechanisms inducing HMGA1 and downstream pathways in MPN. This work should also reveal novel approaches to treat, or even prevent, progression in patients with MPN.