Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2012 May 24;119(21):4971-80. doi: 10.1182/blood-2011-11-389957. Epub 2012 Apr 5.
The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using human mesenchymal stromal cells and endothelial colony-forming cells implanted subcutaneously into immunodeficient mice. We demonstrate the engraftment of human normal and leukemic cells engraft into the human extramedullary bone marrow. When normal hematopoietic cells are engrafted into the model, only discrete areas of the BM are hypoxic, whereas leukemia engraftment results in widespread severe hypoxia, just as recently reported by us in human leukemias. Importantly, the hematopoietic cell engraftment could be altered by genetical manipulation of the bone marrow microenvironment: Extramedullary bone marrow in which hypoxia-inducible factor 1α was knocked down in mesenchymal stromal cells by lentiviral transfer of short hairpin RNA showed significant reduction (50% ± 6%; P = .0006) in human leukemic cell engraftment. These results highlight the potential of a novel in vivo model of human BM microenvironment that can be genetically modified. The model could be useful for the study of leukemia biology and for the development of novel therapeutic modalities aimed at modifying the hematopoietic microenvironment.
造血细胞与骨髓（BM）微环境之间的相互作用在正常和恶性造血以及耐药性中起着关键作用。这些 BM 龛内的相互作用是独特的，对于开发新的治疗方法可能很重要。在这里，我们描述了使用皮下植入免疫缺陷小鼠的人间质基质细胞和内皮祖细胞来发育骨髓外骨和骨髓。我们证明了人类正常和白血病细胞的植入物植入到人类骨髓外骨髓中。当正常造血细胞被植入模型中时，只有 BM 的离散区域缺氧，而白血病植入物则导致广泛的严重缺氧，正如我们最近在人类白血病中报道的那样。重要的是，通过骨髓微环境的基因操作可以改变造血细胞的植入：通过慢病毒转导短发夹 RNA 使间质基质细胞中缺氧诱导因子 1α 敲低的骨髓外骨中，人类白血病细胞植入物显著减少（50%±6%；P=0.0006）。这些结果突出了可遗传修饰的新型人类 BM 微环境体内模型的潜力。该模型可用于研究白血病生物学和开发旨在修饰造血微环境的新型治疗方式。
