Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell Stem Cell. 2017 Oct 5;21(4):547-555.e8. doi: 10.1016/j.stem.2017.07.015.
Hematologic malignancies are driven by combinations of genetic lesions that have been difficult to model in human cells. We used CRISPR/Cas9 genome engineering of primary adult and umbilical cord blood CD34 human hematopoietic stem and progenitor cells (HSPCs), the cells of origin for myeloid pre-malignant and malignant diseases, followed by transplantation into immunodeficient mice to generate genetic models of clonal hematopoiesis and neoplasia. Human hematopoietic cells bearing mutations in combinations of genes, including cohesin complex genes, observed in myeloid malignancies generated immunophenotypically defined neoplastic clones capable of long-term, multi-lineage reconstitution and serial transplantation. Employing these models to investigate therapeutic efficacy, we found that TET2 and cohesin-mutated hematopoietic cells were sensitive to azacitidine treatment. These findings demonstrate the potential for generating genetically defined models of human myeloid diseases, and they are suitable for examining the biological consequences of somatic mutations and the testing of therapeutic agents.
血液系统恶性肿瘤是由多种遗传病变驱动的，这些病变在人类细胞中很难建模。我们使用 CRISPR/Cas9 基因组工程对成人和脐带血 CD34 人类造血干祖细胞（HSPC）进行基因编辑，这些细胞是髓系前恶性和恶性疾病的起源细胞，然后将其移植到免疫缺陷小鼠中，以生成克隆性造血和肿瘤发生的遗传模型。携带有髓系恶性肿瘤中观察到的基因（包括黏合复合物基因）组合突变的人类造血细胞产生了免疫表型定义的肿瘤克隆，能够进行长期、多谱系重建和连续移植。利用这些模型研究治疗效果，我们发现 TET2 和黏合复合物突变的造血细胞对阿扎胞苷治疗敏感。这些发现表明有潜力生成人类髓系疾病的基因定义模型，并且这些模型适合研究体细胞突变的生物学后果和测试治疗药物。
