Stromal Interactions and Leukemic Risk in Myelodysplastic Syndromes

骨髓增生异常综合征中的基质相互作用和白血病风险

• 批准号: 8897103
• 负责人: Honami Naora
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897103
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Anemia; Archives; Bioinformatics; Biological; Biological Markers; Blast Cell; Blood Cells; Bone Marrow; Bone Marrow Cells; Carcinogen exposure; Carcinogens; Cell Differentiation process; Cell Lineage; Cells; Clinical; Clinical Management; Diagnosis; Differential Diagnosis; Disease; Dissection; Dysmyelopoietic Syndromes; Dysplasia; Early Diagnosis; Engraftment; Evolution; Exhibits; Exposure to; Fiber; Fibrosis; Foundations; Genes; Goals; Growth; Hematological Disease; Hematopathology; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeobox Genes; Human; Inflammatory; Lesion; Link; Mediating; Megakaryocyte Proliferation; Megakaryocytes; Megakaryocytopoieses; Mission; Modeling; Molecular; Mus; Myelofibrosis; Nuclear; Outcome; Pathogenesis; Patients; Physicians; Play; Prognostic Marker; Reaction; Reporting; Research; Retrospective Studies; Risk; Risk Assessment; Role; Scientist; Signal Pathway; Signal Transduction; Specimen; Staging; Tissues; Transforming Growth Factors; c-myc Genes; clinically significant; erythroid differentiation; high risk; improved; innovation; insight; leukemia; neoplastic; neoplastic cell; overexpression; programs; public health relevance; stem cell biology; tool; transcription factor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) comprise a group of hematopoietic stem cell disorders that have been etiologically linked to exposure to carcinogens and evolve into acute myeloid leukemia (AML) in approximately 30% of cases. Bone marrow fibrosis is an inflammatory stromal reaction that substantially reduces leukemia-free survival of MDS patients. However, the mechanisms that accelerate AML evolution in patients who have MDS with fibrosis are poorly understood. Treatment of MDS when fibrosis is minimal greatly improves outcomes, but there are no molecular tools for distinguishing this disease at its early stage from other hematologic disorders that have similar morphologic features. Homeobox genes encode transcription factors that control cell lineage-specification and are aberrantly expressed in many types of tumors and pre-neoplastic lesions. In recent studies, we have identified that several homeobox genes promote tumorigenesis by deregulating a variety of signaling pathways that control tumor-stroma interactions. DLX4 is a homeobox gene that has been reported to be induced by carcinogen exposure and to be frequently overexpressed in AML. Our broad hypothesis is that DLX4 accelerates AML evolution in patients who have MDS with fibrosis by stimulating inflammatory signaling. In Aim 1, we will evaluate whether DLX4 expression in hematopoietic progenitor cells stimulates inflammatory signaling, induces MDS with fibrosis, and leads to AML evolution in mouse engraftment models. In Aim 2, we will evaluate the relationship between DLX4 expression, inflammatory signaling, fibrosis and AML evolution in a retrospective study of clinical specimens of MDS. If our study is successful, DLX4 could be a potential biomarker for distinguishing early-stage MDS with fibrosis from other morphologically similar diseases that have low risks of AML evolution. With our multi-disciplinary team of experts in homeobox genes, hematopathology and clinical management of MDS, this study will provide valuable insights into the molecular pathogenesis of MDS and its propensity for AML evolution.

 描述(申请人提供)：骨髓增生异常综合征(MDS)包括一组造血干细胞疾病，在病因学上与致癌物质的接触有关，并在大约30%的病例中演变为急性髓系白血病(AML)。骨髓纤维化是一种炎性间质反应，可显著降低MDS患者的无白血病存活率。然而，在伴有纤维化的MDS患者中，加速AML演变的机制还知之甚少。当纤维化程度很小时，对MDS的治疗极大地改善了预后，但在疾病的早期阶段，没有分子工具可以将其与具有相似形态特征的其他血液系统疾病区分开来。同源框基因编码控制细胞谱系特征的转录因子，在许多类型的肿瘤和癌前病变中异常表达。在最近的研究中，我们已经确定了几个同源盒基因通过解除对控制肿瘤-间质相互作用的各种信号通路的调控来促进肿瘤的发生。DLX4是一种同源异型盒基因，已被报道由致癌物暴露诱导，并在急性髓细胞白血病中频繁过表达。我们的广泛假设是，DLX4通过刺激炎症信号来加速伴有纤维化的MDS患者的AML演变。在目标1中，我们将评估DLX4在造血祖细胞中的表达是否刺激炎症信号，诱导纤维化的MDS，并导致AML在小鼠移植模型中的演变。在目标2中，我们将通过对MDS临床标本的回顾性研究，评估DLX4表达、炎症信号、纤维化和AML演变之间的关系。如果我们的研究成功，DLX4可能成为一种潜在的生物标记物，用于区分早期纤维化MDS和其他形态相似的疾病，这些疾病的AML演变风险较低。随着我们在MDS的同源框基因、血液病理学和临床治疗方面的多学科专家团队的参与，这项研究将为MDS的分子发病机制及其AML演变的倾向提供有价值的见解。