Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support. Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support

Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. There is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem, and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared to ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared to ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells. Overall design: Three bone marrow derived MSC samples isolated from three different AML patients and three bone marrow derived MSC isolated from three different ND control donors resulted in reduction of hematopoietic stem cell content.

骨髓间充质基质细胞（bone marrow mesenchymal stromal cells, MSCs）是造血微环境龛的重要组成成分之一。现有体外研究证据表明，骨髓MSCs能够支持白血病祖细胞的增殖与存活，并帮助其抵抗细胞毒性治疗。然而，白血病骨髓来源的MSCs与正常MSCs的差异机制，以及白血病干细胞与祖细胞如何影响MSCs，目前仍未完全阐明。本研究对比了正常供体（normal donor, ND）来源与急性髓系白血病（acute myelogenous leukemia, AML）来源的MSCs，发现AML-MSCs的成脂潜能显著提升，且其支持白血病祖细胞存活的能力也得到增强。为探究潜在的分子改变，本研究开展了RNA测序（RNA-Seq）分析。基因本体论（Gene ontology）与通路分析结果显示，与ND-MSCs相比，AML-MSCs中失调的生物学通路包含成脂过程。与ND-MSCs相比，AML-MSCs中SOX9与EGR2的表达水平均显著下调。上调SOX9的表达可降低AML-MSCs的成脂潜能，并削弱其支持AML祖细胞的能力。上述研究结果表明，AML-MSCs具备增强白血病祖细胞支持能力的成脂潜能。总体实验设计：从3名不同急性髓系白血病患者及3名不同正常供体对照中分离得到骨髓来源MSCs样本，该样本可导致造血干细胞含量降低。