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（由适用提供）：骨髓增生性综合征（MDS）包括一组造血干细胞疾病，这些造血干细胞疾病在病因上与暴露于致癌物有关，并在大约30％的情况下发展为急性髓样白血病（AML）。骨髓纤维化是一种炎症性基质反应，可大大降低MDS患者无白血病的存活率。然而，对患有纤维化的MD的患者加速AML进化的机制知之甚少。当纤维化最低效果时，MDS的处理，但是没有分子工具可以将这种疾病与其他具有相似形态特征的血液学疾病区分开。同型基因编码控制细胞谱系指定的转录因子，并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，我们已经确定了几个同源基因基因通过消除控制肿瘤 - 细胞瘤相互作用的各种信号通路来促进肿瘤发生。 DLX4是一种同源基因基因，据报道是由致癌物暴露诱导的，并且在AML中经常过表达。我们广泛的假设是，通过刺激炎症信号传导，DLX4在具有纤维化的患者中加速了AML的进化。在AIM 1中，我们在AIM 2中，我们将评估DLX4表达，炎症信号传导，纤维化和AML演化之间的关系，在对MD的临床标本的回顾性研究中。如果我们的研究成功，DLX4可能是将纤维化的早期MDS与其他形态相似的疾病区分开的潜在生物标志物，这些疾病具有低AML进化风险。借助我们在同型基因基因，血管病理学和MDS临床管理方面的多学科专家团队，本研究将为MDS的分子发病机理及其对AML进化的希望提供宝贵的见解。