Edwards Donna M, Mitchell Dana K, Abdul-Sater Zahi, Chan Ka-Kui, Sun Zejin, Sheth Aditya, He Ying, Jiang Li, Yuan Jin, Sharma Richa, Czader Magdalena, Chin Pei-Ju, Liu Yie, de Cárcer Guillermo, Nalepa Grzegorz, Broxmeyer Hal E, Clapp D Wade, Sierra Potchanant Elizabeth A
Department of Pediatrics, Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN, United States.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Oncol. 2021 Nov 5;11:752933. doi: 10.3389/fonc.2021.752933. eCollection 2021.
Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis , the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in mice by introducing heterozygosity of the key spindle assembly checkpoint regulator . mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than mice. We utilized hematopoietic stem cell transplantation to propagate AML in irradiated healthy mice to model -deficient AMLs arising in the non-FA population. Compared to cells from mice, those from mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies , show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.
范可尼贫血（FA）是一种基因组不稳定和癌症相关疾病。除了DNA损伤修复外，现在已知FA通路蛋白对于在有丝分裂期间维持准确的染色体分离至关重要。虽然在FA相关致癌过程中受损的DNA损伤修复已被广泛研究，但FA通路缺陷继发的有丝分裂异常的致癌作用仍未完全了解。为了研究有丝分裂失调在FA通路缺陷恶性肿瘤中的作用，我们通过引入关键纺锤体组装检查点调节因子的杂合性，在小鼠中遗传加剧了基线有丝分裂缺陷。小鼠存活，但死于急性髓系白血病（AML），因此比小鼠更好地重现了FA患者髓系恶性肿瘤的高风险。我们利用造血干细胞移植在受辐照的健康小鼠中繁殖AML，以模拟非FA人群中出现的 -缺陷AML。与来自小鼠的细胞相比，来自小鼠的细胞有丝分裂错误增加，但DNA交联剂超敏反应相当，表明小鼠的癌症表型是由易出错的细胞分裂引起的，而不是DNA损伤修复缺陷的加剧。我们发现FANCC增强了内源性MAD2对前中期动粒的靶向作用，提示了FANCC依赖的纺锤体组装检查点调节如何防止染色体错误分离的机制。全外显子测序揭示了人类FA相关骨髓增生异常综合征（MDS）/AML与在小鼠中发生的AML之间的相似性。总之，这些数据阐明了有丝分裂失调在FA通路缺陷恶性肿瘤中的作用，展示了FANCC如何通过以细胞周期依赖的方式调节MAD2动粒靶向来调整纺锤体组装检查点变阻器，并建立了两种新的小鼠模型用于AML的临床前研究。
