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（由申请人提供）：骨髓增生异常综合征（MDS）包括一组造血干细胞疾病，其病因与暴露于致癌物有关，约30%的病例演变为急性髓性白血病（AML）。骨髓纤维化是一种炎症性基质反应，可显著降低MDS患者的无白血病生存期。然而，加速MDS伴纤维化患者AML演变的机制尚不清楚。当纤维化最小时，MDS的治疗极大地改善了结局，但是没有分子工具用于在早期阶段将这种疾病与具有相似形态学特征的其他血液学疾病区分开。同源框基因编码控制细胞谱系特化的转录因子，并且在许多类型的肿瘤和肿瘤前病变中异常表达。在最近的研究中，我们已经确定，一些同源异型盒基因促进肿瘤发生的各种信号通路，控制肿瘤间质相互作用的失调。DLX4是一种同源异型盒基因，据报道其可由致癌物暴露诱导，并在AML中频繁过表达。我们的广泛假设是DLX4通过刺激炎症信号传导加速MDS伴纤维化患者的AML演变。在目的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传导，诱导MDS伴纤维化，并导致小鼠移植模型中的AML演变。在目标2中，我们将在MDS临床标本的回顾性研究中评估DLX4表达、炎症信号传导、纤维化和AML演变之间的关系。如果我们的研究成功，DLX4可能是一种潜在的生物标志物，用于区分早期MDS伴纤维化与其他形态学相似的疾病，这些疾病的AML演变风险较低。我们的多学科专家团队在同源异型盒基因，血液病理学和MDS的临床管理，这项研究将提供有价值的见解MDS的分子发病机制及其AML演变的倾向。