Mukherjee Sanjay, Ali Abdullah Mahmood, Murty Vundavalli V, Raza Azra
Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Department of Pathology and Cell Biology, and Institute for Cancer Genetics, Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Med Oncol. 2022 Apr 28;39(5):65. doi: 10.1007/s12032-022-01652-9.
Giant cells with polyploidy, termed polyploid giant cells, have been observed during normal growth, development, and pathologic states, such as solid cancer progression and resistance to therapy. Functional studies of polyploidal giant cancer cells (PGCC) provided evidence that they arise when normal diploid cells are stressed, show stem cell-like properties, and give rise to tumors. In the present study, we report in K562 leukemia cell line that introduction of the hotspot K700E mutation in the gene SF3B1 using CRISPR/Cas9 method results in an increased frequency of multinucleated polyploid giant cells resistant to chemotherapeutic agent and serum starvation stress. These giant cells with higher ploidy are distinct from multinucleated megakaryocytes, are proliferative, and are characterized by increased accumulation of mitochondria. PGCC have been previously documented in solid tumors. This is the first report describing PGCCs in a cell line derived from a liquid cancer where increased frequency of PGCCs is linked to a specific genetic event. Since SF3B1 mutations are predominantly seen in MDS and other hematologic malignancies, our current findings will have significant clinical implications.
具有多倍体的巨细胞，即多倍体巨细胞，已在正常生长、发育以及病理状态（如实体癌进展和对治疗的抗性）过程中被观察到。对多倍体巨癌细胞（PGCC）的功能研究表明，它们在正常二倍体细胞受到应激时产生，具有干细胞样特性，并能引发肿瘤。在本研究中，我们报告在K562白血病细胞系中，使用CRISPR/Cas9方法在基因SF3B1中引入热点K700E突变，导致对化疗药物和血清饥饿应激具有抗性的多核多倍体巨细胞频率增加。这些具有更高倍性的巨细胞不同于多核巨核细胞，具有增殖性，并且其特征是线粒体积累增加。PGCC先前已在实体瘤中被记录。这是第一份描述源自液体癌的细胞系中的PGCC的报告，其中PGCC频率增加与特定遗传事件相关。由于SF3B1突变主要见于骨髓增生异常综合征和其他血液系统恶性肿瘤，我们目前的发现将具有重要的临床意义。
