STAT3 inhibition as a therapeutic strategy against MDS stem cells

骨髓增生异常综合征(MDS)通常是一种无法治愈的血液系统疾病 具有引发疾病的干细胞，这些干细胞不能通过传统疗法消除，需要 以潜在的治疗策略为目标。我们最近证明了这一反常现象 造血干细胞在MDS中扩增，可在表型缓解和 可以预测复发。STAT3是一种转录因子，在MDS中高表达 干细胞和高表达与预后不良相关的一大群 病人。我们还获得了概念验证数据，即抑制STAT3可以靶向恶性肿瘤 干细胞，同时保留健康对照的干细胞和祖细胞，从而确定其为潜在的 MDS的治疗靶点。为了全面研究这一途径在MDS中的作用，目标1 将确定STAT3在MDS中疾病始发干细胞生长中的功能作用 确定该通路的临床相关抑制剂在大的原发肿瘤队列中的疗效 人体样本。此外，一种临床适用的、反义的体内外疗效 抑制剂(AZD-9150)对大量初级MDS样本的作用将与 临床和突变亚型，以确定将对STAT3抑制敏感的亚群。 患者来源的MDS异种移植也将用于确定体内疗效。目标2将 通过以下方法确定STAT3在体内启动异型增生/疾病进展中的需求 两种MDS小鼠模型中STAT3基因缺失。以及NUP-Hoxd13型号；a 我们新近建立和诱导的MDS异型增生和转化的新模型 通过杂合子PU1增强子缺失，将用于研究STAT3缺失对 疾病启动干细胞和疾病进展。目标3将确定下游 MDS中STAT3激活的效应因子。ChIP-SEQ和转录特征分析的结合将 用于识别STAT3激活的直接靶点，将在 MDS型号。我们还将确定MCL-1作为下游抗凋亡靶点的作用。 MDS干细胞中STAT3的激活。关键下游效应器的识别将有所改进 我们对MDS中STAT3通路的分子理解将有助于开发 更具体和更有效的策略来抑制这一途径。总而言之，这些研究将 研究STAT3通路在MDS发病机制中的作用，并确定其作为一种 针对MDS中未成熟的、疾病始发细胞的治疗靶点。

Myelodysplastic syndromes (MDS) are generally incurable hematologic disorders 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. STAT3 is a transcription factor that was found to be overexpressed in MDS stem cells and higher expression was associated with an adverse prognosis in a large cohort of patients. We also obtained proof-of-concept data that inhibition of STAT3 can target malignant stem cells while sparing healthy control stem and progenitors, thus identifying it as a potential therapeutic target in MDS. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of STAT3 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, in vitro and in vivo efficacy of a clinically applicable, anti-sense inhibitor (AZD-9150) against a large number of primary MDS samples will be correlated with clinical and mutational subtypes to identify subsets that will be sensitive to STAT3 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for STAT3 in initiation of dysplasia/disease progression in vivo by genetic deletion of STAT3 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 STAT3 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the downstream effectors of STAT3 activation in MDS. Combination of Chip-seq and transcriptomic profiling will be used to identify direct targets of STAT3 activation, that will tested in functional assays in MDS models. We will also determine the role of MCL-1 as a downstream anti-apoptotic target of STAT3 activation in MDS stem cells. Identification of critical downstream effectors will improve our molecular understanding of the STAT3 pathway in MDS and will be instrumental to develop more specific and potent strategies to inhibit this pathway. Taken together, these studies will study the role of the STAT3 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.