Alteration Analysis of Bone Marrow Mesenchymal Stromal Cells from De Novo Acute Myeloid Leukemia Patients at Diagnosis
Alteration Analysis of Bone Marrow Mesenchymal Stromal Cells from De Novo Acute Myeloid Leukemia Patients at Diagnosis
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DOI：
10.1089/scd.2016.0295
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发表时间：
2017-05-15
影响因子：
4
通讯作者：
Domenech, Jorge
中科院分区：
文献类型：
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作者：
Desbourdes, Laura;Javary, Joaquim;Domenech, Jorge
骨髓 (BM) 来源的间充质基质细胞 (MSC) 在多种血液系统疾病中经常表现出改变，例如急性淋巴细胞白血病、急性髓系白血病 (AML) 和骨髓增生异常综合征。在急性白血病中，尚不清楚间充质干细胞的改变是否有助于恶性克隆的发展，或者它们是否只是肿瘤扩张对微环境的影响。我们广泛研究了从诊断时的新发 AML 患者的 BM 中分离的 MSC（L-MSC）的表型（基因和蛋白质表达、细胞凋亡和衰老水平、DNA 双链断裂形成）和功能（增殖和克隆形成潜力、正常和白血病造血支持活性）方面的特征。我们发现，与健康对照的 MSC 相比，L-MSC 的增殖能力降低，凋亡水平增加。 L-MSC 中较长的群体倍增时间与诊断时的 AML 特征（法国-美国-英国类型、细胞遗传学或肿瘤负荷）无关，但与患者年龄有关，并且与较差的患者预后独立相关，细胞遗传学预后特征也是如此。通过分析 93 个基因的表达，我们发现 L-MSC 的增殖缺陷与血管周围特征相关，但以成骨软骨细胞谱系为代价，几个生态位因子的表达较低，例如 KITLG、THPO 和 ANGPT1 基因、细胞粘附分子 VCAM1 以及发育/胚胎基因 BMI1 和 切丁机1。 L-MSC增殖能力与CXCL12、THPO和ANGPT1表达呈正相关，与JAG1表达呈负相关。无论如何，这些变化并不影响它们在体外支持正常造血和改变白血病细胞行为（防止细胞凋亡和静止诱导）的能力。我们的研究结果表明，来自新诊断的 AML 患者的骨髓来源的 MSC 显示出表型和功能的改变，例如可能归因于肿瘤进展的增殖缺陷，但似乎在白血病过程中没有发挥特殊作用。
Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) frequently display alterations in several hematologic disorders, such as acute lymphoid leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes. In acute leukemias, it is not clear whether MSC alterations contribute to the development of the malignant clone or whether they are simply the effect of tumor expansion on the microenvironment. We extensively investigated the characteristics of MSCs isolated from the BM of patients with de novo AML at diagnosis (L-MSCs) in terms of phenotype (gene and protein expression, apoptosis and senescence levels, DNA double-strand break formation) and functions (proliferation and clonogenic potentials, normal and leukemic hematopoiesis-supporting activity). We found that L-MSCs show reduced proliferation capacity and increased apoptosis levels compared with MSCs from healthy controls. Longer population doubling time in L-MSCs was not related to the AML characteristics at diagnosis (French-American-British type, cytogenetics, or tumor burden), but was related to patient age and independently associated with poorer patient outcome, as was cytogenetic prognostic feature. Analyzing, among others, the expression of 93 genes, we found that proliferative deficiency of L-MSCs was associated with a perivascular feature at the expense of the osteo-chondroblastic lineage with lower expression of several niche factors, such as KITLG, THPO, and ANGPT1 genes, the cell adhesion molecule VCAM1, and the developmental/embryonic genes, BMI1 and DICER1. L-MSC proliferative capacity was correlated positively with CXCL12, THPO, and ANGPT1 expression and negatively with JAG1 expression. Anyway, these changes did not affect their in vitro capacity to support normal hematopoiesis and to modify leukemic cell behavior (protection from apoptosis and quiescence induction). Our findings indicate that BM-derived MSCs from patients with newly diagnosed AML display phenotypic and functional alterations such as proliferative deficiency that could be attributed to tumor progression, but does not seem to play a special role in the leukemic process.