Therapeutic targeting of MDS stem cells

MDS是一种与疾病引发干细胞相关的通常无法治愈的血液系统疾病 传统疗法无法消除，需要靶向治疗， 战略布局我们最近证明，异常造血干细胞在造血干细胞中扩增， MDS可在表型缓解期间持续存在，并可预测复发。在初步研究中， 我们证明了白细胞介素8（IL 8）在干细胞中持续和选择性地过表达， MDS患者。IL8受体CXCR2在大型MDS中也显著增加 患者队列，并与预后较差相关。在功能上，IL8/CXCR2通路 通过shRNA介导的敲除或药理学方法消除的抑制 细胞系和原发性MDS样品中的增殖。重要的是，抑制IL8/CXCR2 通路选择性地抑制来自MDS样品的未成熟干细胞，而不影响健康人。 HSC，并且在异种移植物中也表现出功效。为了全面审视 Aim 1将定义IL-8/CXCR2通路对MDS细胞生长的功能作用。 疾病引发的干细胞在MDS中，并确定临床相关的抑制剂的功效， 这一途径在大的原始人类样本队列中。此外，对IL8/CXCR2的应答 用小分子和新的人源化抗体的抑制作用将与临床 突变亚型，以鉴定对IL8/CXCR2抑制敏感的靶向子集。 患者来源的MDS异种移植物也将用于确定体内疗效。目标2将 通过以下方式确定体内异型增生/疾病进展起始对CXCR2的需求： 在两种MDS小鼠模型中CXCR2基因缺失。沿着NUP-HOXD 13模型; a 我们最近开发的MDS发育异常和转化的新模型， 1增强子缺失，将用于研究CXCR2缺失对CXCR2表达的影响。 疾病引发干细胞和疾病进展。目标3将确定 IL 8-CXCR2通路的激活并确定其在MDS中的下游效应物。IL8是一种 已知的先天免疫信号级联的组成部分，我们将确定是否上游 免疫激活剂、IL1RAP、TLR和IRAK1/4驱动IL8/CXCR2的过度激活 骨髓增生异常综合症的途径。我们还将评估PI3激酶的激活和功能意义 和MAP激酶途径作为MDS中IL 8/CXCR2途径的下游效应物。采取 总之，这些研究将研究IL 8/CXCR2通路在MDS发病机制中的作用， 确定其作为MDS中未成熟的疾病起始细胞的治疗靶点的潜力。

MDS is a generally incurable hematologic disorder associated with disease initiating stem cells that are not eliminated by conventional therapies and need to be targeted for potentially curative strategies. We recently demonstrated that aberrant hematopoietic stem cells are expanded in MDS, can persist during phenotypic remissions and can predict relapse. In preliminary studies, we demonstrate that Interleukin 8 (IL8) is consistently and selectively overexpressed in stem cells from MDS patients. The receptor for IL8, CXCR2, is also significantly increased in large MDS patient cohorts and is associated with a worse prognosis. Functionally, IL8/CXCR2 pathway inhibition by either shRNA-mediated knockdown or pharmacologic approaches abrogated proliferation in cell lines and primary MDS samples. Importantly, inhibition of the IL8/CXCR2 pathway selectively inhibited immature stem cells from MDS samples without an effect on healthy HSCs, and also had demonstrated efficacy in xenografts. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of IL-8/CXCR2 pathway on growth of disease initiating stem cells in MDS and determine the efficacy of clinically relevant inhibitors of this pathway in large cohort of primary human samples. Additionally, responses to IL8/CXCR2 inhibition with small molecules and a novel humanized antibody will be correlated with clinical and mutational subtypes to identify targetable subsets that will be sensitive to IL8/CXCR2 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for CXCR2 in initiation of dysplasia/disease progression in vivo by genetic deletion of CXCR2 in two mouse models of MDS. Along with the NUP-HOXD13 model; a novel model of MDS dysplasia and transformation which we have recently developed, induced by heterozygous PU.1 enhancer deletion, will be used to study the effect of CXCR2 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the mechanisms of activation of the IL8-CXCR2 pathway and determine its downstream effectors in MDS. IL8 is a known component of innate immune signaling cascades, and we will determine whether upstream immune activators, IL1RAP, TLRs and IRAK1/4 are driving overactivation of the IL8/CXCR2 pathway in MDS. We will also evaluate the activation and functional significance of PI3Kinase and MAP kinase pathways as downstream effectors of the IL8/CXCR2 pathway in MDS. Taken together, these studies will study the role of the IL8/CXCR2 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.