Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n= 44) and patients diagnosed with myeloproliferative neoplasia (n= 11), myelodysplastic syndromes (n= 16), or acute myeloid leukemia (n= 25) and B-Non-Hodgkin lymphoma (n= 9) with BM infiltration and acute lymphoblastic leukemia (n= 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets.
髓系与淋巴系肿瘤均具有以原发性或继发性效应浸润骨髓的特征，易导致造血功能不全。目前，克隆性恶性细胞在骨髓中抑制正常造血干细胞与祖细胞（HSPCs）的机制尚未阐明。鉴于间充质基质细胞（MSCs）在骨髓微环境造血调控中的关键作用，推测MSCs在血液肿瘤发病机制中亦发挥重要作用。本研究旨在揭示髓系与淋巴系肿瘤来源MSCs中促进疾病进展、抑制HSPCs的共同作用机制，以开发针对这些机制的干预策略。研究分析了健康供者（n=44）及确诊为骨髓增殖性肿瘤（n=11）、骨髓增生异常综合征（n=16）、急性髓系白血病（n=25）、伴骨髓浸润的B细胞非霍奇金淋巴瘤（n=9）及急性淋巴细胞白血病（n=9）患者来源MSCs的功能特性，并进行RNA测序。结果显示所有疾病组MSCs的生长与分化能力均下降。RNA测序可区分疾病组与对照组，但明确显示存在重叠的差异表达基因，包括对细胞生长、成骨分化及造血至关重要的BMP/TGF和WNT信号通路关键因子。恶性细胞培养上清液可诱导健康MSCs出现类似功能改变，提示这些因子参与疾病进展。本研究最终成功鉴定出具有潜在治疗价值的共性作用因子。
Overlapping Stromal Alterations in Myeloid and Lymphoid Neoplasms
肿瘤(癌症)患者之家