Targeting HMGA1-Mediated Progression and Immune Evasion in Myeloproliferative Diseases

我建议阐明高迁移率族A1（HMGA 1）染色质调节剂介导的机制 骨髓增生性肿瘤（MPN）的疾病进展。MPN是血液疾病引起的， 造血干细胞和祖细胞（HSPC）中的突变导致克隆扩增。人士 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， 其中与不良临床结果相关。然而，进展的潜在机制仍然存在， 不太了解。引起MPN的最常见的遗传病变是Janus激酶2（JAK 2）的突变， 造血生长因子受体的专性酪氨酸激酶。这种突变（表示为JAK 2 V617 F）导致 增强信号转导和转录激活因子（STAT 3）的磷酸化，导致 不受控制的血细胞生成。重要的是，抑制JAK/STAT信号转导可改善症状，但 而不是阻止进展。在这里，我专注于HMGA 1作为MPN进展中JAK/STAT信号传导的关键介质。 我们认为HMGA 1促进MPN进展的科学前提基于以下令人信服的事实： 初步结果：1）HMGA 1是一种染色质调节剂，其“打开”染色质以诱导STAT 3和其他转录因子。 参与人血细胞祖细胞克隆扩增的基因。2)阻断MPN中的JAK/STAT信号传导 细胞减少HMGA 1，表明JAK/STAT信号诱导HMGA 1，HMGA 1前馈 放大STAT 3信号。3)hmga 1过表达导致小鼠血细胞祖细胞克隆扩增， 随着年龄的增长会发展成白血病4)Hmga 1缺乏减轻JAK 2 V617 F MPN小鼠的进展 5)在人JAK 2 V617 F突变型MPN细胞中，HMGA 1是增殖、克隆形成和白血病所必需的 小鼠中的移植。6)HMGA 1在人HSPC中增加，MPN进展为MF或白血病。7)HMGA1 基于RNA调节参与MPN细胞周期进程和免疫逃避的基因网络 测序结果。8)HMGA 1还与异常生长和免疫相关的基因网络有关。 在实体瘤和其他血液癌症中的逃避。总之，这些有趣的结果支持了 以下假设：1）HMGA 1与STAT 3合作以促进克隆扩增、免疫逃避，以及 MPN进展，2）HMGA 1通过参与增殖和免疫的基因网络驱动进展 3）靶向HMGA 1和STAT 3将防止克隆扩增、免疫逃避和MPN进展。 目的/方法：为了验证这一点，我们提出了以下具体目的：1）为了确定HMGA 1和HMGA 2是否与HMGA 1和HMGA 2相关， STAT 3产生前馈回路以促进MPN进展，2）为了确定HMGA 1如何改变MPN的进展， 3）为了开始测试靶向HMGA 1和STAT 3两者的治疗功效， 防止异常克隆扩增、免疫逃避和MPN进展。 影响：我们希望阐明MPN中诱导HMGA 1和下游通路的机制。这项工作 还应该揭示新的方法来治疗，甚至预防，与MPN患者的进展。

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.